Pharmaceutical Research Laboratories, Toray Industries, Inc., 10-1-6 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
Bioorg Med Chem Lett. 2013 Jun 1;23(11):3154-6. doi: 10.1016/j.bmcl.2013.04.016. Epub 2013 Apr 13.
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.
我们旨在发现一种新型的瞬时受体电位香草酸 1 型 (TRPV1) 拮抗剂，因为这类拮抗剂可能是治疗各种疾病的候选药物。我们对先导化合物 7（人 TRPV1 IC50=411 nM）的结构进行了修饰，将其吡咯烷基团转化为（羟乙基）甲氨基，这大大提高了抑制活性（15d；人 TRPV1 IC50=33 nM）。此外，15d 改善了体内大鼠的膀胱过度活动。
