Design, synthesis, and biological evaluation of novel biphenyl-4-carboxamide derivatives as orally available TRPV1 antagonists

[Display omitted] A new series of transient receptor potential vanilloid type 1 (TRPV1) antagonists were designed and synthesized from N-(3-hydroxyphenyl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide hydrochloride (8). SAR studies identified (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2018-07, Vol.26 (12), p.3716-3726
Main Authors: Oka, Hiromasa, Yonezawa, Koichi, Kamikawa, Akio, Ikegai, Kazuhiro, Asai, Norio, Shirakami, Shohei, Miyamoto, Satoshi, Watanabe, Toshihiro, Kiso, Tetsuo, Takemoto, Yukihiro, Tamura, Seiji, Kuramochi, Takahiro
Format: Article
Language:English
Subjects:
Administration, Oral
Agonist
Amides - chemistry
Amides - metabolism
Amides - therapeutic use
Anticonvulsants - chemical synthesis
Anticonvulsants - metabolism
Anticonvulsants - therapeutic use
Biphenyl Compounds - chemistry
Biphenyl-4-carboxamide
Cytochrome P-450 CYP3A - chemistry
Cytochrome P-450 CYP3A - metabolism
Drug Design
HEK293 Cells
Humans
Inhibitory Concentration 50
Microsomes, Liver - metabolism
Neuralgia - drug therapy
Neuropathic pain
Oral absorption
Solubility
Structure-Activity Relationship
TRPV Cation Channels - antagonists & inhibitors
TRPV Cation Channels - metabolism
TRPV1 antagonist
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Summary:[Display omitted] A new series of transient receptor potential vanilloid type 1 (TRPV1) antagonists were designed and synthesized from N-(3-hydroxyphenyl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide hydrochloride (8). SAR studies identified (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide hydrochloride (ASP8370, 7), as a compound with high aqueous solubility, satisfactory stability in human liver microsomes, and reduced CYP3A4 inhibition. ASP8370 was selected as a clinical development candidate with significant ameliorative effects on neuropathic pain. SAR studies also revealed the structural mechanisms underlying the switching between TRPV1 antagonism and agonism.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2018.06.001