Fused piperidines as a novel class of potent and orally available transient receptor potential melastatin type 8 (TRPM8) antagonists

  • J Med Chem. 2012 Feb 23;55(4):1593-611. doi: 10.1021/jm2013634.
Nuria A Tamayo  1 ,  Yunxin Bo ,  Vijay Gore ,  Vu Ma ,  Nobuko Nishimura ,  Phi Tang ,  Hong Deng ,  Lana Klionsky ,  Sonya G Lehto ,  Weiya Wang ,  Brad Youngblood ,  Jiyun Chen ,  Tiffany L Correll ,  Michael D Bartberger ,  Narender R Gavva ,  Mark H Norman
Affiliations
  • 1. Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States. [email protected]
PMID: 22329507 DOI: 10.1021/jm2013634
Abstract

The transient receptor potential melastatin type 8 (TRPM8) is a nonselective cation channel primarily expressed in a subpopulation of sensory neurons that can be activated by a wide range of stimuli, including menthol, icilin, and cold temperatures (<25 °C). Antagonism of TRPM8 is currently under investigation as a new approach for the treatment of pain. As a result of our screening efforts, we identified tetrahydrothienopyridine 4 as an inhibitor of icilin-induced calcium influx in CHO cells expressing recombinant rat TRPM8. Exploration of the structure-activity relationships of 4 led to the identification of a potent and orally bioavailable TRPM8 antagonist, tetrahydroisoquinoline 87. Compound 87 demonstrated target coverage in vivo after oral administration in a rat pharmacodynamic model measuring the prevention of icilin-induced wet-dog shakes (WDS).