Usmarapride

Description

Why Usmarapride as a 5-HT4 agonist

• In summary, Usmarapride is easily the best option out of the 5-HT4 agonists, as the others are far worse in pharmacokinetics, mainly in CNS permeability
• Usmarapride (Cb/Cp = 3.8) is significantly more CNS permeable than Prucalopride (Cb/Cp = 0.5), PF-04995274 (Cb/Cp = 0.7), PRX-03140 (Cb/Cp = 1.6), and other past 5-HT4 agonists [x, x]
• Usmarapride has good bioavailability (F = 34%) unlike PF-0499527 (F = 5.4%) and PRX-03140 (F = 2%) [x, x]
• Usmarapride was tested against RS-67333 for sAPPα secretion, which is a neuronal response by 5-HT4, and Usmarapride is more potent [x]
• Oral Usmarapride shows significantly greater 5-HT4 receptor occupancy at lower doses compared to RS-67333 [x]
• Usmarapride has a long 13.2 – 18.8 hr half-life in humans [x]

Suven’s history of creating CNS targeted 5-HT4 agonists

• Suven Life Sciences has the most extensive CNS permeable 5-HT4 agonist research and has been researching to find the best compound since 2012 to find the best balance of affinity, 5-HT4 response (Emax), CNS permeability (Concentration brain/Concentration plasma, a ratio of the agonist inside the brain vs. outside the brain), selectivity, and other pharmacokinetics (F%, Cmax, AUC, t1/2, Vdss, CL) with many studies until they found Usmarapride
• For CNS permeability improvement comparison made by Suven; the best discovered compound was Compound 2D aka PF-04995274 (Cb/Cp = 0.7) in 2012 [x, x], then Compound 5A (Cb/Cp = 0.31) in 2015 [x], then Compound 4O (Cb/Cp = 0.8) in 2018 [x], and then finally Compound 12L aka Usmarapride (Cb/Cp = 3.8) in 2021 [x]