| Literature DB >> 22329507 |
Nuria A Tamayo1, 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.
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).Entities:
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Year: 2012 PMID： 22329507 DOI： 10.1021/jm2013634
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446