Piclamilast is a selective

Binding selectivity

Binding selectivity refers to the differing affinities with which different ligands bind to a substrate forming a complex. A selectivity coefficient is the equilibrium constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate...

 PDE4 inhibitor

PDE4 inhibitor

A phosphodiesterase type 4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 on cyclic adenosine monophosphate . It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in...

. It is comparable to other PDE4 inhibitors for its anti-inflammatory

Anti-inflammatory

Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....

 effects. It has been investigated for its applications to the treatment of conditions such as chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease , also known as chronic obstructive lung disease , chronic obstructive airway disease , chronic airflow limitation and chronic obstructive respiratory disease , is the co-occurrence of chronic bronchitis and emphysema, a pair of commonly co-existing diseases...

, bronchopulmonary dysplasia

Bronchopulmonary dysplasia

Bronchopulmonary dysplasia is a chronic lung disorder that is most common among children who were born prematurely, with low birthweights and who received prolonged mechanical ventilation to treat respiratory distress syndrome...

 and asthma

Asthma

Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...

. It is a second generation compound that exhibits structural functionalities of the PDE4 inhibitors cilomilast

Cilomilast

Cilomilast is a drug which was developed for the treatment of respiratory disorders such as asthma and Chronic Obstructive Pulmonary Disease...

 and roflumilast

Roflumilast

Roflumilast is a drug which acts as a selective, long-acting inhibitor of the enzyme PDE-4. It has antiinflammatory effects and is under development as an orally administered drug for the treatment of inflammatory conditions of the lungs such as asthma, and chronic obstructive pulmonary disease...

. The structure for piclamilast was first elucidated in a 1995 European patent application. The earliest mention of the name "piclamilast" was used in a 1997 publication.

Mechanism of action

Piclamilast functions through the selective inhibition of the four PDE4 isoforms (PDE4A-D). It shows no inhibition of the other PDEs. The PDE4 isoforms are especially important to inflammatory and immunomodulatory cells. They are the most common PDE in inflammatory cells such as mast cells, neutrophils, basophils, eosinophils, T lymphocytes, macrophages, and structural cells such as sensory nerves

Sensory nerves

Sensory nerves are nerves that receive sensory stimuli, such as how something feels and if it is painful, smooth, rough, etc.They are made up of nerve fibers, called sensory fibers .Sensory neurons are neurons that are activated by sensory input Sensory nerves are nerves that receive sensory...

 and epithelial cells. PDE4 hydrolyzes cyclic adenosine monophosphate

Cyclic adenosine monophosphate

Cyclic adenosine monophosphate is a second messenger important in many biological processes...

 (cAMP) to inactive adenosine monophosphate

Adenosine monophosphate

Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...

 (AMP). Inhibition of PDE4 blocks hydrolysis of cAMP thereby increasing levels of cAMP within cells. cAMP suppresses the activity of immune and inflammatory cells. PDE4 inhibition in an induced chronic lung disease murine model was shown to have anti-inflammatory properties, attenuate pulmonary fibrin

Fibrin

Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....

 deposition and vascular alveolar leakage, and prolong survival in hyperoxia-induced neonatal lung injury. A study of PDE4 inhibition in a murine model of allergic asthma showed that piclamilast significantly improves the pulmonary function, airway inflammation and goblet cell

Goblet cell

Goblet cells are glandular simple columnar epithelial cells whose sole function is to secrete mucin, which dissolves in water to form mucus. They use both apocrine and merocrine methods for secretion....

 hyperplasia.

Side effects

Emesis is the most commonly cited side effect

Side effect

In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.Occasionally, drugs are...

 of piclamilast. It has proven difficult to separate the emetic side effects from the therapeutic benefits of several PDE4 inhibitors, including piclamilast.

Chemical synthesis

The preparation steps for synthesis of piclamilast are as follows (both Discovery and Production routes have been documented)

1. Addition of cyclopentyl to isovanillin
   Isovanillin
   Isovanillin is a phenolic aldehyde, an organic compound and isomer of vanillin. It is a selective inhibitor of aldehyde oxidase. It is not a substrate of that enzyme, and is metabolized by aldehyde dehydrogenase into isovanillic acid....
   
    via Williamson ether synthesis
   Williamson ether synthesis
   The Williamson ether synthesis is an organic reaction, forming an ether from an organohalide and an alcohol. This reaction was developed by Alexander Williamson in 1850. Typically it involves the reaction of an alkoxide ion with a primary alkyl halide via an SN2 reaction...
   
   .
2. Oxidation of aldehyde
   Aldehyde
   An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
   
    group to carboxylic acid
   Carboxylic acid
   Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
   
   .
3. Formation of acid chloride by treatment with thionyl chloride
   Thionyl chloride
   Thionyl chloride is an inorganic compound with the formula SOCl2. It is a reactive chemical reagent used in chlorination reactions. It is a colorless, distillable liquid at room temperature and pressure that decomposes above 140 °C. Thionyl chloride is sometimes confused with sulfuryl...
   
   .
4. Formation of amide
   Amide
   In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
   
   by reaction with deprotonated 4-amino-3,5-dichloropyridine.