Discovery of (R)-1-(7-Chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea(A-1165442): A Temperature-Neutral Transient Receptor Potential Vanilloid-1(TRPV1) Antagonist with Analgesic Efficacy.

Thesynthesis and characterization of a series of selective, orallybioavailable 1-(chroman-4-yl)urea TRPV1 antagonists is described.Whereas first-generation antagonists that inhibit all modes of TRPV1activation can elicit hyperthermia, the compounds disclosed hereindo not elevate core body temperature in preclinical models and onlypartially block acid activation of TRPV1. Advancing the SAR of thisseries led to the eventual identification of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea(A-1165442, 52), an analogue that possesses excellentpharmacological selectivity, has a favorable pharmacokinetic profile,and demonstrates good efficacy against osteoarthritis pain in rodents. [ABSTRACT FROM AUTHOR]