Fused Piperidines as a Novel Class of Potent and Orally Available Transient Receptor Potential Melastatin Type 8 (TRPM8) Antagonists
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- 作者：Nuria A. Tamayo ; 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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：February 23, 2012
- 年：2012
- 卷：55
- 期：4
- 页码：1593-1611
- 全文大小：666K
- 年卷期：v.55,no.4(February 23, 2012)
- ISSN：1520-4804
文摘
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 掳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鈥揳ctivity 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).