Description
Why Usmarapride over other 5-HT4 agonist RC candidates
- 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 ± 0.2) is significantly more CNS permeable than Prucalopride (0.5 ± 0.2), PF-04995274 (0.7 ± 0.2), PRX-03140 (1.6 ± 0.4), and other past 5-HT4 agonists [x, x] - Usmarapride has a long half-life of
13.2–18.8 h(different tested doses) [x] - Usmarapride has good bioavailability (F =
34 ± 13%) unlike PF-0499527 (5.4 ± 0.3%) and PRX-03140 (2 ± 0%) [x, x] - Usmarapride was tested against RS-67333 for sAPPα secretion, which is a neuronal 5-HT4 response, and the object recognition test (ORT). Usmarapride is more potent in both tests [x]
- Out of 18 volunteers with tested doses ranging from 10 – 40 mg, only one experienced GI (gastrointestinal) effects. Thus, Usmarapride uniquely lacks undesirable GI effects which is common for 5-HT4 agonists with low CNS permeability like Prucalopride [x, 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 2d or PF-04995274 (Cb/Cp =
0.7 ± 0.2) with a very weak response (Emax =18 ± 9.2%) in 2012 [x, x], then 5a (0.31 ± 0.12) in 2015 [x], then 4o (0.8 ± 0.1) in 2018 [x], and then finally 12l or Usmarapride/SUVN-D4010 (3.8 ± 0.2) in 2021 [x]
