Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
J Med Chem. 2011 Oct 27;54(20):7232-46. doi: 10.1021/jm200808v. Epub 2011 Sep 26.
The bradykinin B1 receptor is rapidly induced upon tissue injury and inflammation, stimulating the production of inflammatory mediators resulting in plasma extravasation, leukocyte trafficking, edema, and pain. We have previously reported on sulfonamide and sulfone-based B1 antagonists containing a privileged bicyclic amine moiety leading to potent series of 2-oxopiperazines. The suboptimal pharmacokinetics and physicochemical properties of the oxopiperazine sulfonamides led us to seek B1 antagonists with improved druglike properties. Using a pharmacophore model containing a bicyclic amine as anchor, we designed a series of amide antagonists with targeted physicochemical properties. This approach led to a novel series of potent phthalazinone B1 antagonists, where we successfully replaced a sulfonamide acceptor with a cyclic carbonyl unit. SAR studies revealed compounds with subnanomolar B1 binding affinity. These compounds demonstrate excellent cross-species PK properties with high oral bioavailability and potent activity in a rabbit biochemical challenge pharmacodynamic study.
缓激肽 B1 受体在组织损伤和炎症时迅速被诱导产生，刺激炎症介质的产生，导致血浆渗出、白细胞迁移、水肿和疼痛。我们之前曾报道过含有特权双环胺部分的基于磺胺和砜的 B1 拮抗剂，这些化合物导致了一系列强效的 2-氧代哌嗪。由于氧代哌嗪磺胺类药物的药代动力学和物理化学性质不理想，我们试图寻找具有改善的类药性的 B1 拮抗剂。我们使用含有双环胺作为锚点的药效团模型，设计了一系列具有靶向物理化学性质的酰胺拮抗剂。这种方法导致了一系列新型的强效酞嗪酮 B1 拮抗剂，其中我们成功地用环状羰基单元替代了磺胺类受体。SAR 研究揭示了具有亚纳摩尔 B1 结合亲和力的化合物。这些化合物在兔生物化学挑战药效动力学研究中表现出优异的跨物种 PK 特性，具有高口服生物利用度和强效活性。
