title: Discovery of potent transient receptor potential vanilloid 1 antagonists: design and synthesis of phenoxyacetamide derivatives.
abstract: We aimed to discover a novel type of transient receptor potential vanilloid 1 (TRPV1) antagonist because such antagonists are possible drug candidates for treating various disorders. We modified the structure of hit compound 7 (human TRPV1 IC50=411 nM) and converted its pyrrolidino group to a (hydroxyethyl)methylamino group, which substantially improved inhibitory activity (15d; human TRPV1 IC50=33 nM). In addition, 15d ameliorated bladder overactivity in rats in vivo.
authors: Pharmaceutical Research Laboratories, Toray Industries, Inc., 10-1-6 Tebiro, Kamakura, Kanagawa 248-8555, Japan. eiki_takahashi@nts.toray.co.jp
authors: Eiki
authors: E
authors: Takahashi
authors: Noriyuki
authors: N
authors: Hirano
authors: Takashi
authors: T
authors: Nagahara
authors: Satoru
authors: S
authors: Yoshikawa
authors: Shinobu
authors: S
authors: Momen
authors: Hiroshi
authors: H
authors: Yokokawa
authors: Ryoji
authors: R
authors: Hayashi
mesh_terms: D000081:Acetamides / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000631:Aminopyridines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D002211:Capsaicin / Q000633:toxicity; D003556:Cystitis / Q000139:chemically induced / Q000188:drug therapy; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000081:Acetamides; D000631:Aminopyridines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C030686:acetamide; D002211:Capsaicin