Optimization of potency and pharmacokinetic properties of tetrahydroisoquinoline transient receptor potential melastatin 8 (TRPM8) antagonists
| Autor: | Vu Van Ma, Maosheng Zhang, Nuria A. Tamayo, Vijay Keshav Gore, Weiya Wang, Phi Tang, Holger Monenschein, Daniel B. Horne, Mark H. Norman, Michael D. Bartberger, Yunxin Bo, Jeffrey Clarine, Thomas T. Nguyen, Carl Davis, Beth D. Youngblood, Matthew R. Kaller, Sonya G. Lehto, Narender R. Gavva, Nobuko Nishimura |
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| Rok vydání: | 2014 |
| Předmět: |
Male
TRPM Cation Channels Pyrimidinones Pharmacology Motor Activity Rats Sprague-Dawley chemistry.chemical_compound Transient receptor potential channel Dogs In vivo Tetrahydroisoquinolines Drug Discovery TRPM8 Potency Animals Humans Tissue Distribution Behavior Animal Tetrahydroisoquinoline Circular Dichroism Icilin Cold pressor test Stereoisomerism Rats Cold Temperature chemistry Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization Microsomes Liver Molecular Medicine Menthol |
| Zdroj: | Journal of medicinal chemistry. 57(7) |
| ISSN: | 1520-4804 |
| Popis: | Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system. TRPM8 is the predominant mammalian cold temperature thermosensor and is activated by cold temperatures ranging from 8 to 25 °C and cooling compounds such as menthol or icilin. TRPM8 antagonists are being pursued as potential therapeutics for treatment of pain and bladder disorders. This manuscript outlines new developments in the SAR of a lead series of 1,2,3,4-tetrahydroisoquinoline derivatives with emphasis on strategies to improve pharmacokinetic properties and potency. Selected compounds were profiled in two TRPM8 target-specific in vivo coverage models in rats (the icilin-induced wet dog shake model and the cold pressor test). Compound 45 demonstrated robust efficacy in both pharmacodynamic models with ED90 values |
| Databáze: | OpenAIRE |
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