Document Report Card

ID: ALA2029325

Journal: J Med Chem

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

Authors: Tamayo NA, Bo Y, Gore V, Ma V, Nishimura N, Tang P, Deng H, Klionsky L, Lehto SG, Wang W, Youngblood B, Chen J, Correll TL, Bartberger MD, Gavva NR, Norman MH.

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).

CiteXplore: 22329507

DOI: 10.1021/jm2013634