具有口服生物利用度且能穿透中枢神经系统的联苯氨基环丙烷甲酰胺缓激肽B1受体拮抗剂的研发。

Development of orally bioavailable and CNS penetrant biphenylaminocyclopropane carboxamide bradykinin B1 receptor antagonists.

作者信息

Kuduk Scott D, Di Marco Christina N, Chang Ronald K, Wood Michael R, Schirripa Kathy M, Kim June J, Wai Jenny M C, DiPardo Robert M, Murphy Kathy L, Ransom Richard W, Harrell C Meacham, Reiss Duane R, Holahan Marie A, Cook Jacquelynn, Hess J Fred, Sain Nova, Urban Mark O, Tang Cuyue, Prueksaritanont Thomayant, Pettibone Douglas J, Bock Mark G

机构信息

Department of Medicinal Chemistry, Merck Research Laboratories, Sumneytown Pike, P.O. Box 4, West Point, Pennsylvania 19486, USA.

出版信息

J Med Chem. 2007 Jan 25;50(2):272-82. doi: 10.1021/jm061094b.

DOI:10.1021/jm061094b

PMID:17228869

Abstract

A series of biphenylaminocyclopropane carboxamide based bradykinin B1 receptor antagonists has been developed that possesses good pharmacokinetic properties and is CNS penetrant. Discovery that the replacement of the trifluoropropionamide in the lead structure with polyhaloacetamides, particularly a trifluoroacetamide, significantly reduced P-glycoprotein mediated efflux for the series proved essential. One of these novel bradykinin B1 antagonists (13b) also exhibited suitable pharmacokinetic properties and efficient ex vivo receptor occupancy for further development as a novel approach for the treatment of pain and inflammation.

摘要

已经开发出一系列基于联苯氨基环丙烷甲酰胺的缓激肽B1受体拮抗剂，它们具有良好的药代动力学性质且能够穿透中枢神经系统。发现用多卤代乙酰胺，特别是三氟乙酰胺取代先导结构中的三氟丙酰胺，可显著降低该系列中P-糖蛋白介导的外排，这一点被证明至关重要。这些新型缓激肽B1拮抗剂之一（13b）也表现出合适的药代动力学性质和有效的体外受体占有率，可作为治疗疼痛和炎症的新方法进一步开发。