Boehm Markus, Beaumont Kevin, Jones Rhys, Kalgutkar Amit S, Zhang Liying, Atkinson Karen, Bai Guoyun, Brown Janice A, Eng Heather, Goetz Gilles H, Holder Brian R, Khunte Bhagyashree, Lazzaro Sarah, Limberakis Chris, Ryu Sangwoo, Shapiro Michael J, Tylaska Laurie, Yan Jiangli, Turner Rushia, Leung Siegfried S F, Ramaseshan Mahesh, Price David A, Liras Spiros, Jacobson Matthew P, Earp David J, Lokey R Scott, Mathiowetz Alan M, Menhaji-Klotz Elnaz
Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.
Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
J Med Chem. 2017 Dec 14;60(23):9653-9663. doi: 10.1021/acs.jmedchem.7b01028. Epub 2017 Oct 30.
The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small-molecule modulators of CXCR7 have been reported, peptidic macrocycles may provide advantages in terms of potency, selectivity, and reduced off-target activity. We produced a series of peptidic macrocycles that incorporate an N-linked peptoid functionality where the peptoid group enabled us to explore side-chain diversity well beyond that of natural amino acids. At the same time, theoretical calculations and experimental assays were used to track and reduce the polarity while closely monitoring the physicochemical properties. This strategy led to the discovery of macrocyclic peptide-peptoid hybrids with high CXCR7 binding affinities (K < 100 nM) and measurable passive permeability (P > 5 × 10 cm/s). Moreover, bioactive peptide 25 (K = 9 nM) achieved oral bioavailability of 18% in rats, which was commensurate with the observed plasma clearance values upon intravenous administration.
趋化因子受体CXCR7是多种疾病的一个有吸引力的靶点。虽然已经报道了几种CXCR7的小分子调节剂，但肽类大环化合物在效力、选择性和降低脱靶活性方面可能具有优势。我们制备了一系列包含N-连接类肽功能的肽类大环化合物，其中类肽基团使我们能够探索远远超出天然氨基酸的侧链多样性。同时，利用理论计算和实验测定来跟踪和降低极性，同时密切监测物理化学性质。这一策略导致发现了具有高CXCR7结合亲和力（K < 100 nM）和可测量的被动通透性（P > 5 × 10 cm/s）的大环肽-类肽杂合物。此外，生物活性肽25（K = 9 nM）在大鼠中实现了18%的口服生物利用度，这与静脉给药后观察到的血浆清除率值相当。
