Biswas Kaustav, Li Aiwen, Chen Jian Jeffrey, D'Amico Derin C, Fotsch Christopher, Han Nianhe, Human Jason, Liu Qingyian, Norman Mark H, Riahi Bobby, Yuan Chester, Suzuki Hideo, Mareska David A, Zhan James, Clarke David E, Toro Andras, Groneberg Robert D, Burgess Laurence E, Lester-Zeiner Dianna, Biddlecome Gloria, Manning Barton H, Arik Leyla, Dong Hong, Huang Ming, Kamassah Augustus, Loeloff Richard, Sun Hong, Hsieh Feng-Yin, Kumar Gondi, Ng Gordon Y, Hungate Randall W, Askew Benny C, Johnson Eileen
Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
J Med Chem. 2007 May 3;50(9):2200-12. doi: 10.1021/jm070055c. Epub 2007 Apr 5.
The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure-activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the beta-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38, was also active in a rabbit B1 receptor cellular assay. Furthermore, compound 38 displayed in vivo activity in two rabbit models, a pharmacodynamic model with a blood pressure readout and an efficacy model of inflammatory pain.
缓激肽B1受体在组织损伤和/或炎症后被诱导产生。该受体的拮抗剂已被作为治疗慢性疼痛的有前景的候选药物进行研究。我们已鉴定出含有手性苯并二氢吡喃二胺部分的芳基磺酰胺，它们是人类B1受体的强效拮抗剂。我们之前报道的先导化合物2作为概念验证分子，但存在药代动力学性质不佳的问题。在代谢谱分析的指导下，我们进行了构效关系研究，并鉴定出了2的强效类似物。磺酰胺部分的变化表明，3-和3,4-二取代的芳基磺酰胺更受青睐，而在苄胺位置，较大的仲胺和叔胺对于B1受体的活性更有利。修饰分子的β-氨基酸核心导致发现了具有改善的体外药代动力学性质的高效化合物。在人类受体上最有效的类似物化合物38，在兔B1受体细胞试验中也具有活性。此外，化合物38在两种兔模型中表现出体内活性，一种是具有血压读数的药效学模型，另一种是炎性疼痛的疗效模型。
