MK-8318, a Potent and Selective CRTh2 Receptor Antagonist in Asthma

Asthma is the most common inflammatory disease Nowadays. Unfortunately, Asthma affects millions of people all over the world.

Chemoattractant receptor-homologous molecule expresses on TH2 cells. The molecule is a G-protein coupled receptor, which binds to the ligand prostaglandin D2 (PGD2). The molecular is expressed on various cell types. These cells include eosinophils, mast cells, and basophils. The G-protein coupled receptor and PGD2 involve in allergic inflammation and eosinophil activation. Moreover, The PGD2 induced chemotaxis, degranulation, and cytokine production exclusively exert through CRTh2 receptors. The modulation of CRTh2 receptors results in reducing excessive allergic responses. CRTH2 antagonism attenuates nasal allergic inflammation. The CRTH2 antagonists target toward eosinophilic asthma. CRTH2 antagonists provide a practical alternative to biological treatments for patients with severe asthma.

For the purpose, orally administered CRTH2 antagonists are in clinical development for the treatment of asthma. On the one hand, CRTH2 activation increases intracellular calcium levels. On the other hand, CRTH2 activation reduces intracellular cyclic adenosine monophosphate levels. Besides, CRTH2 activation activates various signaling pathways including PKC, PI3K, and p38 MAPK. As a result, many scientists want to synthesize small-molecule antagonists, which targets CRTH2 receptor for oral administration. These antagonists show sufficient potency in preclinical studies for asthma clinical trials. All in all, MK-8318 is a potent and selective CRTh2 receptor antagonist. MK-8318 is suitable for once-daily oral dosing. MK-8318 is a preclinical candidate due to its favorable PK profile suitable for once daily oral dosing and clean ancillary profiles.