2. Academic Validation
  3. 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

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

  • J Med Chem. 2014 Sep 11;57(17):7412-24. doi: 10.1021/jm500916t.
Eric A Voight 1,  Arthur R Gomtsyan,  Jerome F Daanen,  Richard J Perner,  Robert G Schmidt,  Erol K Bayburt,  Stanley DiDomenico,  Heath A McDonald,  Pamela S Puttfarcken,  Jun Chen,  Torben R Neelands,  Bruce R Bianchi,  Ping Han,  Regina M Reilly,  Pamela H Franklin,  Jason A Segreti,  Richard A Nelson,  Zhi Su,  Andrew J King,  James S Polakowski,  Scott J Baker,  Donna M Gauvin,  LaGeisha R Lewis,  Joseph P Mikusa,  Shailen K Joshi,  Connie R Faltynek,  Philip R Kym,  Michael E Kort
Affiliations

Affiliation

  • 1 Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
PMID: 25100568 DOI: 10.1021/jm500916t
Abstract

The synthesis and characterization of a series of selective, orally bioavailable 1-(chroman-4-yl)urea TRPV1 antagonists is described. Whereas first-generation antagonists that inhibit all modes of TRPV1 activation can elicit hyperthermia, the compounds disclosed herein do not elevate core body temperature in preclinical models and only partially block acid activation of TRPV1. Advancing the SAR of this series 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 excellent pharmacological selectivity, has a favorable pharmacokinetic profile, and demonstrates good efficacy against osteoarthritis pain in rodents.

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