Optimization of Potency and Pharmacokinetic Properties of Tetrahydroisoquinoline Transient Receptor Potential Melastatin 8 (TRPM8) Antagonists

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 cool...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2014-04, Vol.57 (7), p.2989-3004
Main Authors: Horne, Daniel B, Tamayo, Nuria A, Bartberger, Michael D, Bo, Yunxin, Clarine, Jeffrey, Davis, Carl D, Gore, Vijay K, Kaller, Matthew R, Lehto, Sonya G, Ma, Vu V, Nishimura, Nobuko, Nguyen, Thomas T, Tang, Phi, Wang, Weiya, Youngblood, Beth D, Zhang, Maosheng, Gavva, Narender R, Monenschein, Holger, Norman, Mark H
Format: Article
Language:English
Subjects:
Animals
Behavior, Animal - drug effects
Circular Dichroism
Cold Temperature
Dogs
Humans
Male
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Motor Activity - drug effects
Pyrimidinones - pharmacology
Rats
Rats, Sprague-Dawley
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Stereoisomerism
Tetrahydroisoquinolines - chemistry
Tetrahydroisoquinolines - pharmacokinetics
Tetrahydroisoquinolines - pharmacology
Tissue Distribution
TRPM Cation Channels - antagonists & inhibitors
TRPM Cation Channels - metabolism
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Summary: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
ISSN:0022-2623
1520-4804
DOI:10.1021/jm401955h