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

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

Affiliation

  • 1 Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States. ntamayo@amgen.com
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).

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