Discovery and development of CCR5 receptor antagonists
Encyclopedia
CCR5 receptor antagonists are a class of small molecule
s that antagonize
the CCR5 receptor. The C-C motif chemokine receptor CCR5 is involved in the HIV
entry process. Hence antagonists of this receptor have potential therapeutic applications in the treatment of HIV infections.
The life cycle of the Human Immunodeficiency Virus (HIV)
presents potential targets for drug therapy, one of them being the viral entry pathway. The C-C motif chemokine receptors CCR5
and CXCR4
are the main chemokine receptors involved in the HIV
entry process. These receptors belong to the seven transmembrane G-protein-coupled receptor (GPCR) family and are predominantly expressed on human T-cells, dendritic cells and macrophages. They play an important role as co-receptors that HIV type 1 (HIV-1) uses to attach to cells before viral fusion and entry into host cells. HIV isolates can be divided into R5 and X4 strains. R5 strain is when the virus uses the co-receptor CCR5 and X4 strain is when it uses CXCR4. The location of CCR5 receptors at the cell surface, both large and small molecules have the potential to interfere with the CCR5-viral interaction and inhibit viral entry into human cells.
was the observation that a small percentage of high-risk populations showed either resistance or delayed development of the disease. This population was found to have a mutation
(CCR5-Δ32) in the gene that codes for the CCR5 receptor which results in almost complete resistance against HIV-1 infection and scientists then discovered the key role of the cell surface receptors
CCR5 and CXCR4
in successful viral fusion and infection. In 1996, it was demonstrated that CCR5 serves as a co-receptor for the most commonly transmitted HIV-1 strains, R5. This type of virus is predominant during the early stages of infection and remains the dominant form in over 50% of late stage HIV-1 infected patients, however R5 strains can eventually evolve into X4 as the disease progresses. This information led to the development of a new class of HIV drugs called CCR5 antagonists.
) to the CD4+ T-cell receptor, which produces a conformational change in gp120 and allows it to bind to CCR5, thereby triggering glycoprotein 41 (gp41
) mediated fusion of the viral envelope
with the cell membrane
and the nucleocapsid enters the host cell (Figure 1). CCR5 co-receptor antagonists prevent HIV-1 from entering and infecting immune cells by blocking CCR5 cell-surface receptor. Small molecule
antagonists of CCR5 bind to a hydrophobic pocket formed by the transmembrane helices of the CCR5 receptor. They are thought to interact with the receptor in an allosteric manner locking the receptor in a conformation that prohibits its co-receptor function.
ion channel, as inhibition of hERG can lead to QT interval
prolongation. Abnormality in the interval can increase the risk of developing ventricular arrhythmias. Many CCR5 antagonists have been introduced by pharmaceutical companies but few of them have actually reached human efficacy studies, for example AstraZeneca
, Novartis
, Merck and Takeda have used these GPRC compound collections to develop a potent CCR5 antagonist but none of them have reached clinical trials. Three pharmaceutical companies were racing for the first approved small molecule CCR5 antagonist; GlaxoSmithKline
(GSK), with their compound aplaviroc
, Schering-Plough
with vicriviroc
and Pfizer
with maraviroc
. All the compounds reached clinical trials in humans but only maraviroc
has been approved by the U.S. Food and Drug Administration (FDA). In the following section the development of these three compounds will be discussed.
is originated from a class of spirodiketopiperazine derivatives. Figure 2 shows the molecular structure of the lead compound and the final compound aplaviroc. The lead compound showed good potency in blocking CCR5 in a number of R5 HIV strains and against multi-drug resistant strains. The problem with this compound was not its CCR5 selectivity but the oral bioavailability. This led to further development of the molecule and the result was a compound named aplaviroc. Unfortunately despite the promising preclinical and early clinical results some severe liver toxicity was observed in the treatment of naive and treatment-experienced patients that led to the discontinuation in further development of aplaviroc.
. The lead compound contained a piperazine
scaffold and was a potent muscarinic acetylcholine receptor
(M2) antagonist with modest CCR5 activity. The changes that were made on the left hand side of the lead compound and the addition of a methyl group on the piperazine group ((S)-methylpiperazine) resulted in the intermediate compound that had good affinity for CCR5 receptors but very little affinity for muscarinic activity, however, the compound did show affinity for the hERG ion channel. Further reconstruction led to the development of the final compound vicriviroc, when Schering discovered that the pyridyl N-oxide on the intermediate could be replaced by 4,6-dimethylpyrimidine carboxamide. Vicriviroc had an excellent selectivity for CCR5 receptors over muscarinic and hERG affinity was greatly reduced. Phase I clinical trial of vicriviroc gave promising results, so a phase II study in the treatment of naive patients was initiated. The phase II study was discontinued since there was a viral breakthrough in the vicriviroc group compared to the control group. These results suggested that vicriviroc was not effective in the treatment of treatment-naive patients compared to current treatments. Another phase II clinical study was performed in treatment-experienced patients. The results were that vicriviroc did have strong antiviral activity but five instances of cancer
among the participants were reported, however, the study was continued since there was lack of causal association of the malignancies and vicriviroc. In late 2009 vicriviroc was assigned in phase III studies in treatment-experienced patients, and in phase II studies in treatment for naive patients.
in their search for a good starting point for a small molecule CCR5 antagonist. Their screening resulted in a compound that presented weak affinity and no antiviral activity but represented a good starting point for further optimization. Compounds 1-9 in table 1 show the development of maraviroc
in few steps. The chemical structure of the starting molecule is presented as compound 1. Their first focus was to minimize CYP2D6
activity of the molecule and to reduce its lipophilicity. They replaced the imidazopyridine
with benzimidazole
and the benzhydril group was swapped out for a benzamide
. The outcome was compound 2. That compound showed good binding potency and the start of an antiviral activity. Further SAR (structure-activity relationship
) optimization of the amide region and identifying the enantiomer
ic preference led to the cyclobutyl amide structure in compound 3. However, the problem with the CYP2D6 activity of the compound was still unacceptable so they had to perform further SAR optimization that determined that the [3.2.1]-azabicycloamine (topane) could replace the aminopiperidine moiety. This change in the chemical structure led to compound 4. Compound 4 had no CYP2D6 activity while preserving excellent binding affinity and antiviral activity. Although compound 4 showed promising results it demonstrated 99% inhibition on the hERG
ion channel. That inhibition was unacceptable since it can lead to QTc interval
prolongation. The research team then did a few modifications to see which part of the molecule played a role in the hERG affinity. Compound 5 shows an analogue that they synthesized which contained an oxygen bridgehead in the tropane
ring; however, that reconstruction did not have an effect on the hERG affinity. They then focused on the polar surface area in the molecule to dial out the hERG affinity. These efforts resulted in compound 6. That compound preserved desired antiviral activity and was selective against the hERG inhibition but the problem was its bioavailability. Reduction in the lipophilicity, by replacing the benzimidazol group with a substituted triazole group gave compound 7. Compound 7 had shown a significant reduction in lipophilicity and maintained the antiviral activity but again, with the introduction of a cyclobutyl group the compound showed hERG inhibition. Changing the ring size in compound 7 from a cyclobutyl unit to a cyclopentyl unit in compound 8 led to a significant increase in antiviral activity and loss of hERG affinity. Further development led to discovery of a 4,4’-difluorocyclohexylamide also known as maraviroc. Maraviroc preserved excellent antiviral activity, whilst demonstrating no significant hERG binding affinity. The lack of hERG binding affinity was predicted to be because of the large size of the cyclohexyl group and the high polarity
of the fluoro substituents. In August 2007 the FDA approved the first CCR5 antagonist, maraviroc discovered and developed by Pfizer.
model was developed for a large series of piperidine
- and piperazine
-based CCR5 antagonists by Schering-Plough Research Institute. Their hypothesis consisted of mostly five features, two hydrogen bond acceptors, marked C and D in figure 4 and three hydrophobic groups, A, B and E in figure 4. Part B usually has a basic nitrogen group. The model was validated using diverse set of six CCR5 antagonists from five different pharmaceutical companies. The best model correctly predicted these compounds as being highly active. It is possible to use the model as a tool in virtual screening for new small molecular CCR5 antagonists and also to predict biological activities of compounds prior to undertaking their costly synthesis.
86 and 248 (Trp86, Trp248), tyrosine
108 and 251 (Tyr108, Tyr251), phenylalanine
109 (phe109), threonine
195 (Thr195), isoleucine
198 (Ile198), glutamic acid
283 (Glu283). CCR5 antagonists are very different in shape and electrostatic potential although they all share the same binding pocket. The interesting thing about the binding of these molecules is that they exhibit significantly different binding modes, although they all establish an extensive interaction network with CCR5.
while the interaction with phenylalanine (Phe109) is predicted to be hydrophopic. Tyrosine (Tyr108) is thought to interact with the phenyl group on maraviroc through a parallel displaced interaction. The interaction between maraviroc and isoleucine (Ile198) is predicted to be mostly hydrophobic in nature and the interaction between maraviroc and tyrosine (Tyr251) is very limited.
have discovered a novel series of potent CCR5 small molecule antagonists. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Combination of the spiropiperidine template with pharmacophore elements from both aplaviroc, and Schering’s CCR5 antagonist program, led to the initial lead compound in this series. Further development of that lead compound led to the discovery of compound A in figure 7 - A compound that possesses a good selectivity and pharmacokinetic properties.
The CCR5 antagonist INCB009471 has nanomolar activity against HIV-1 in vitro. This compound demonstrated potent and prolonged antiviral activity against R5-tropic HIV-1 when given 200 mg once daily dose for 14 days. These findings supported further clinical development of INCB009471 and they have since progressed to phase IIb clinical trials. As of 2009 the study of this compound is inactive and no further studies are planned at this time.
Small molecule
In the fields of pharmacology and biochemistry, a small molecule is a low molecular weight organic compound which is by definition not a polymer...
s that antagonize
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
the CCR5 receptor. The C-C motif chemokine receptor CCR5 is involved in the HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
entry process. Hence antagonists of this receptor have potential therapeutic applications in the treatment of HIV infections.
The life cycle of the Human Immunodeficiency Virus (HIV)
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
presents potential targets for drug therapy, one of them being the viral entry pathway. The C-C motif chemokine receptors CCR5
CCR5
C-C chemokine receptor type 5, also known as CCR5, is a protein that in humans is encoded by the CCR5 gene. CCR5 is a member of the beta chemokine receptors family of integral membrane proteins...
and CXCR4
CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
are the main chemokine receptors involved in the HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
entry process. These receptors belong to the seven transmembrane G-protein-coupled receptor (GPCR) family and are predominantly expressed on human T-cells, dendritic cells and macrophages. They play an important role as co-receptors that HIV type 1 (HIV-1) uses to attach to cells before viral fusion and entry into host cells. HIV isolates can be divided into R5 and X4 strains. R5 strain is when the virus uses the co-receptor CCR5 and X4 strain is when it uses CXCR4. The location of CCR5 receptors at the cell surface, both large and small molecules have the potential to interfere with the CCR5-viral interaction and inhibit viral entry into human cells.
History
Since the discovery of HIV in the 1980s, remarkable progress has been made in the development of novel antiviral drugs. The trigger for the discovery of the CCR5 antagonistsReceptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
was the observation that a small percentage of high-risk populations showed either resistance or delayed development of the disease. This population was found to have a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
(CCR5-Δ32) in the gene that codes for the CCR5 receptor which results in almost complete resistance against HIV-1 infection and scientists then discovered the key role of the cell surface receptors
Membrane receptor
Cell surface receptors are specialized integral membrane proteins that take part in communication between the cell and the outside world...
CCR5 and CXCR4
CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
in successful viral fusion and infection. In 1996, it was demonstrated that CCR5 serves as a co-receptor for the most commonly transmitted HIV-1 strains, R5. This type of virus is predominant during the early stages of infection and remains the dominant form in over 50% of late stage HIV-1 infected patients, however R5 strains can eventually evolve into X4 as the disease progresses. This information led to the development of a new class of HIV drugs called CCR5 antagonists.
Mechanism of action
HIV enters host cells in the blood by attaching itself to receptors on the surface of the CD4+ cell. Viral entry to the CD4+ cell begins with attachment of the R5 HIV-1 glycoprotein 120 (gp120Gp120
Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons...
) to the CD4+ T-cell receptor, which produces a conformational change in gp120 and allows it to bind to CCR5, thereby triggering glycoprotein 41 (gp41
Gp41
gp41 is a subunit of the envelope protein complex of retroviruses, including Human immunodeficiency virus and Simian-Human immunodeficiency virus. This glycoprotein subunit remains non-covalently-bound to gp120, and provides the second step by which HIV enters the cell...
) mediated fusion of the viral envelope
Viral envelope
Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells...
with the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
and the nucleocapsid enters the host cell (Figure 1). CCR5 co-receptor antagonists prevent HIV-1 from entering and infecting immune cells by blocking CCR5 cell-surface receptor. Small molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
antagonists of CCR5 bind to a hydrophobic pocket formed by the transmembrane helices of the CCR5 receptor. They are thought to interact with the receptor in an allosteric manner locking the receptor in a conformation that prohibits its co-receptor function.
Drug development
As mentioned, the CCR5 receptor is a G-protein coupled receptor (GPCR) and before the discovery of CCR5’s role in HIV infection many pharmaceutical companies had already built a substantial collection of compounds that target GPCRs. Some of these compounds provided an excellent starting point for CCR5 antagonists but then needed further optimization to gain better potency, pharmacokinetic properties and better CCR5 selectivity. One of the biggest problems was the affinity for the hERGHERG
hERG is a gene that codes for a protein known as Kv11.1 potassium ion channel...
ion channel, as inhibition of hERG can lead to QT interval
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
prolongation. Abnormality in the interval can increase the risk of developing ventricular arrhythmias. Many CCR5 antagonists have been introduced by pharmaceutical companies but few of them have actually reached human efficacy studies, for example AstraZeneca
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
, Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
, Merck and Takeda have used these GPRC compound collections to develop a potent CCR5 antagonist but none of them have reached clinical trials. Three pharmaceutical companies were racing for the first approved small molecule CCR5 antagonist; GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
(GSK), with their compound aplaviroc
Aplaviroc
Aplaviroc is a CCR5 entry inhibitor developed for the treatment of HIV infection. It is developed by GlaxoSmithKlineIn October 2005, all studies of aplaviroc were discontinued due to liver toxicity concerns...
, Schering-Plough
Schering-Plough
Schering-Plough Corporation was a United States-based pharmaceutical company. It was founded in 1851 by Ernst Christian Friedrich Schering as Schering AG in Germany. In 1971, the Schering Corporation merged with Plough to form Schering-Plough. On November 4, 2009 Merck & Co...
with vicriviroc
Vicriviroc
Vicriviroc, previously named SCH 417690 and SCH-D, is a pyrimidine CCR5 entry inhibitor of HIV-1. It was developed by the pharmaceutical company Schering-Plough. Merck decided to not pursue regulatory approval for use in treatment-experienced patients because the drug did not meet primary efficacy...
and Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
with maraviroc
Maraviroc
Maraviroc is an antiretroviral drug in the CCR5 receptor antagonist class used in the treatment of HIV infection. It is also classed as an entry inhibitor.-Mechanism of action:...
. All the compounds reached clinical trials in humans but only maraviroc
Maraviroc
Maraviroc is an antiretroviral drug in the CCR5 receptor antagonist class used in the treatment of HIV infection. It is also classed as an entry inhibitor.-Mechanism of action:...
has been approved by the U.S. Food and Drug Administration (FDA). In the following section the development of these three compounds will be discussed.
Aplaviroc
AplavirocAplaviroc
Aplaviroc is a CCR5 entry inhibitor developed for the treatment of HIV infection. It is developed by GlaxoSmithKlineIn October 2005, all studies of aplaviroc were discontinued due to liver toxicity concerns...
is originated from a class of spirodiketopiperazine derivatives. Figure 2 shows the molecular structure of the lead compound and the final compound aplaviroc. The lead compound showed good potency in blocking CCR5 in a number of R5 HIV strains and against multi-drug resistant strains. The problem with this compound was not its CCR5 selectivity but the oral bioavailability. This led to further development of the molecule and the result was a compound named aplaviroc. Unfortunately despite the promising preclinical and early clinical results some severe liver toxicity was observed in the treatment of naive and treatment-experienced patients that led to the discontinuation in further development of aplaviroc.
Vicriviroc
Schering-Plough identified an active compound during screening. Figure 3 shows the molecular structure of the lead compound, intermediate compound and the final compound vicrivirocVicriviroc
Vicriviroc, previously named SCH 417690 and SCH-D, is a pyrimidine CCR5 entry inhibitor of HIV-1. It was developed by the pharmaceutical company Schering-Plough. Merck decided to not pursue regulatory approval for use in treatment-experienced patients because the drug did not meet primary efficacy...
. The lead compound contained a piperazine
Piperazine
Piperazine is an organic compound that consists of a six-membered ring containing two opposing nitrogen atoms. Piperazine exists as small alkaline deliquescent crystals with a saline taste....
scaffold and was a potent muscarinic acetylcholine receptor
Muscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
(M2) antagonist with modest CCR5 activity. The changes that were made on the left hand side of the lead compound and the addition of a methyl group on the piperazine group ((S)-methylpiperazine) resulted in the intermediate compound that had good affinity for CCR5 receptors but very little affinity for muscarinic activity, however, the compound did show affinity for the hERG ion channel. Further reconstruction led to the development of the final compound vicriviroc, when Schering discovered that the pyridyl N-oxide on the intermediate could be replaced by 4,6-dimethylpyrimidine carboxamide. Vicriviroc had an excellent selectivity for CCR5 receptors over muscarinic and hERG affinity was greatly reduced. Phase I clinical trial of vicriviroc gave promising results, so a phase II study in the treatment of naive patients was initiated. The phase II study was discontinued since there was a viral breakthrough in the vicriviroc group compared to the control group. These results suggested that vicriviroc was not effective in the treatment of treatment-naive patients compared to current treatments. Another phase II clinical study was performed in treatment-experienced patients. The results were that vicriviroc did have strong antiviral activity but five instances of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
among the participants were reported, however, the study was continued since there was lack of causal association of the malignancies and vicriviroc. In late 2009 vicriviroc was assigned in phase III studies in treatment-experienced patients, and in phase II studies in treatment for naive patients.
Maraviroc
Pfizer turned to high-throughput screeningHigh-throughput screening
High-throughput screening is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry. Using robotics, data processing and control software, liquid handling devices, and sensitive detectors, High-Throughput Screening allows a...
in their search for a good starting point for a small molecule CCR5 antagonist. Their screening resulted in a compound that presented weak affinity and no antiviral activity but represented a good starting point for further optimization. Compounds 1-9 in table 1 show the development of maraviroc
Maraviroc
Maraviroc is an antiretroviral drug in the CCR5 receptor antagonist class used in the treatment of HIV infection. It is also classed as an entry inhibitor.-Mechanism of action:...
in few steps. The chemical structure of the starting molecule is presented as compound 1. Their first focus was to minimize CYP2D6
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
activity of the molecule and to reduce its lipophilicity. They replaced the imidazopyridine
Imidazopyridine
The imidazopyridines are a class of drugs defined by their chemical structure. They are generally GABAA receptor agonists, however recently proton pump inhibitors in this class have been developed as well. Despite usually being similar to them in effect, they are not chemically related to...
with benzimidazole
Benzimidazole
Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene and imidazole. The most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. Benzimidazole, in...
and the benzhydril group was swapped out for a benzamide
Benzamide
Benzamide is an off-white solid with the chemical formula of C6H5CONH2. It is a derivative of benzoic acid. It is slightly soluble in water, and soluble in many organic solvents.- External links :* *...
. The outcome was compound 2. That compound showed good binding potency and the start of an antiviral activity. Further SAR (structure-activity relationship
Structure-activity relationship
The structure–activity relationship is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical groups responsible for evoking a target biological effect in the organism...
) optimization of the amide region and identifying the enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
ic preference led to the cyclobutyl amide structure in compound 3. However, the problem with the CYP2D6 activity of the compound was still unacceptable so they had to perform further SAR optimization that determined that the [3.2.1]-azabicycloamine (topane) could replace the aminopiperidine moiety. This change in the chemical structure led to compound 4. Compound 4 had no CYP2D6 activity while preserving excellent binding affinity and antiviral activity. Although compound 4 showed promising results it demonstrated 99% inhibition on the hERG
HERG
hERG is a gene that codes for a protein known as Kv11.1 potassium ion channel...
ion channel. That inhibition was unacceptable since it can lead to QTc interval
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
prolongation. The research team then did a few modifications to see which part of the molecule played a role in the hERG affinity. Compound 5 shows an analogue that they synthesized which contained an oxygen bridgehead in the tropane
Tropane
Tropane is a nitrogenous bicyclic organic compound. It is mainly known for a group of alkaloids derived from it , which include, among others, atropine and cocaine. Both alkaloids contain tropinone from which tropane is a derivate...
ring; however, that reconstruction did not have an effect on the hERG affinity. They then focused on the polar surface area in the molecule to dial out the hERG affinity. These efforts resulted in compound 6. That compound preserved desired antiviral activity and was selective against the hERG inhibition but the problem was its bioavailability. Reduction in the lipophilicity, by replacing the benzimidazol group with a substituted triazole group gave compound 7. Compound 7 had shown a significant reduction in lipophilicity and maintained the antiviral activity but again, with the introduction of a cyclobutyl group the compound showed hERG inhibition. Changing the ring size in compound 7 from a cyclobutyl unit to a cyclopentyl unit in compound 8 led to a significant increase in antiviral activity and loss of hERG affinity. Further development led to discovery of a 4,4’-difluorocyclohexylamide also known as maraviroc. Maraviroc preserved excellent antiviral activity, whilst demonstrating no significant hERG binding affinity. The lack of hERG binding affinity was predicted to be because of the large size of the cyclohexyl group and the high polarity
Chemical polarity
In chemistry, polarity refers to a separation of electric charge leading to a molecule or its chemical groups having an electric dipole or multipole moment. Polar molecules interact through dipole–dipole intermolecular forces and hydrogen bonds. Molecular polarity is dependent on the difference in...
of the fluoro substituents. In August 2007 the FDA approved the first CCR5 antagonist, maraviroc discovered and developed by Pfizer.
Pharmacophore
The predictive pharmacophorePharmacophore
thumb|right|300px|An example of a pharmacophore model.A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule....
model was developed for a large series of piperidine
Piperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
- and piperazine
Piperazine
Piperazine is an organic compound that consists of a six-membered ring containing two opposing nitrogen atoms. Piperazine exists as small alkaline deliquescent crystals with a saline taste....
-based CCR5 antagonists by Schering-Plough Research Institute. Their hypothesis consisted of mostly five features, two hydrogen bond acceptors, marked C and D in figure 4 and three hydrophobic groups, A, B and E in figure 4. Part B usually has a basic nitrogen group. The model was validated using diverse set of six CCR5 antagonists from five different pharmaceutical companies. The best model correctly predicted these compounds as being highly active. It is possible to use the model as a tool in virtual screening for new small molecular CCR5 antagonists and also to predict biological activities of compounds prior to undertaking their costly synthesis.
Binding
CCR5 is a member of G-protein-coupled, seven transmembrane segment receptors. The structure of the receptor comprises seven-helix bundle in the transmembrane region, these regions are labeled I-VII in figure 5 and 6. The CCR5 antagonists are predicted to bind to a putative binding pocket which is buried inside the transmembrane domain, enclosed by the seven transmembrane helices. The binding pocket is very hydrophobic with multiple aromatic residues lining the pocket. The key residues are tryptophanTryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
86 and 248 (Trp86, Trp248), tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
108 and 251 (Tyr108, Tyr251), phenylalanine
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
109 (phe109), threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
195 (Thr195), isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
198 (Ile198), glutamic acid
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
283 (Glu283). CCR5 antagonists are very different in shape and electrostatic potential although they all share the same binding pocket. The interesting thing about the binding of these molecules is that they exhibit significantly different binding modes, although they all establish an extensive interaction network with CCR5.
Aplaviroc
The putative binding mode for aplaviroc is shown in figure 5. The key saltbridge interaction between aplaviroc and Glu283 is predicted to be quite weak compared to other CCR5 antagonists. The hydroxyl group on aplaviroc forms a strong hydrogen bond to the polar residue Thr195. This H-bond interaction is the strongest with aplaviroc compared to other CCR5 antagonists. The cyclohexyl group in the aplaviroc structure is predicted to interact with the receptor in a hydrophobic pocket formed by Ile198, Thr15 and Phe109 and is thought to show quite strong hydrophobic interactions. The researchers predict that the t-butyl group of aplaviroc is buried within the helical bundle through strong hydrophobic interaction with multiple aromatic residues of the CCR5 receptor.Maraviroc
The putative binding mode for maraviroc is shown in figure 6. The strongest interaction is estimated to be between maraviroc and glutamic acid (Glu283) through a strong salt-bridge interaction. The interaction between tryptophan (Trp86) and maraviroc involves T-shaped π-π stackingStacking
Stacking may refer to:* Stacking * Stacking , a 2011 game from Double Fine involving matryoshka dolls* A gang signal made with the hands* Sport stacking, played using plastic cups* A film directed and produced by Martin Rosen...
while the interaction with phenylalanine (Phe109) is predicted to be hydrophopic. Tyrosine (Tyr108) is thought to interact with the phenyl group on maraviroc through a parallel displaced interaction. The interaction between maraviroc and isoleucine (Ile198) is predicted to be mostly hydrophobic in nature and the interaction between maraviroc and tyrosine (Tyr251) is very limited.
Aplaviroc
Aplaviroc has a unique feature of preserving two of the natural chemokine protein ligands binding to CCR5 and subsequent activation, whereas maraviroc and the other antagonists almost fully block chemokine-CCR5 interactions. This kind of interference is so far considered to be safe, and individuals that naturally lack CCR5 do not show any obvious health problems. However, to limit the toxicity and side effects of CCR5 antagonists it would be ideal to be able to preserve the chemokine receptor function. Consequently, it should be of interest to design inhibitors that specifically disrupt CCR5-gp120 binding but do not affect the CCR5 chemokine activation.Other CCR5 antagonists
Development of new CCR5 antagonists continues, both for their antiviral effects and also for potential utility in a variety of autoimmune indications. Researchers at OnoOno
ONO, Ono or Ōno may refer to:-People with the Japanese surname:In Japanese, Ono and Ōno are different place names and also common surnames. Ono means "small field" and Ōno means "large field". Both are used as Japanese surnames.* Ono no Azumabito ONO, Ono or Ōno may refer to:-People with the...
have discovered a novel series of potent CCR5 small molecule antagonists. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Combination of the spiropiperidine template with pharmacophore elements from both aplaviroc, and Schering’s CCR5 antagonist program, led to the initial lead compound in this series. Further development of that lead compound led to the discovery of compound A in figure 7 - A compound that possesses a good selectivity and pharmacokinetic properties.
The CCR5 antagonist INCB009471 has nanomolar activity against HIV-1 in vitro. This compound demonstrated potent and prolonged antiviral activity against R5-tropic HIV-1 when given 200 mg once daily dose for 14 days. These findings supported further clinical development of INCB009471 and they have since progressed to phase IIb clinical trials. As of 2009 the study of this compound is inactive and no further studies are planned at this time.
See also
- CenicrivirocCenicrivirocCenicriviroc is an experimental drug candidate for the treatment of HIV infection. It is being developed by Takeda Pharmaceutical and Tobira Therapeutics....
- CD4CD4CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
- CCL5
- Subtypes of HIVSubtypes of HIVOne of the obstacles to treatment of the human immunodeficiency virus is its high genetic variability. HIV can be divided into two major types, HIV type 1 and HIV type 2 . HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to...
- HIV tropismHIV tropismHIV tropism refers to the cell type that the human immunodeficiency virus infects and replicates in. HIV tropism of a patient's virus is measured by the Trofile assay....
- Discovery and development of non-nucleoside reverse transcriptase inhibitorsDiscovery and development of non-nucleoside reverse transcriptase inhibitorsNon-nucleoside reverse-transcriptase inhibitors are antiretroviral drugs used in the treatment of human immunodeficiency virus . NNRTIs inhibit reverse transcriptase , an enzyme that controls the replication of the genetic material of HIV...
- Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitorsDiscovery and development of nucleoside and nucleotide reverse-transcriptase inhibitorsDiscovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors began in the 1980s when the AIDS epidemic hit Western societies. NRTIs inhibit the reverse transcriptase , an enzyme that controls the replication of the genetic material of the human immunodeficiency virus ....