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Discovery of Potent and Orally Bioavailable Macrocyclic Peptide–Peptoid Hybrid CXCR7 Modulators
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-10-30 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01028 Markus Boehm 1 , Kevin Beaumont 1 , Rhys Jones 1 , Amit S. Kalgutkar 1 , Liying Zhang 1 , Karen Atkinson 2 , Guoyun Bai 2 , Janice A. Brown 2 , Heather Eng 2 , Gilles H. Goetz 2 , Brian R. Holder 2 , Bhagyashree Khunte 2 , Sarah Lazzaro 2 , Chris Limberakis 2 , Sangwoo Ryu 2 , Michael J. Shapiro 2 , Laurie Tylaska 2 , Jiangli Yan 2 , Rushia Turner 3 , Siegfried S. F. Leung 4, 5 , Mahesh Ramaseshan 5 , David A. Price 1 , Spiros Liras 1 , Matthew P. Jacobson 4 , David J. Earp 5 , R. Scott Lokey 3 , Alan M. Mathiowetz 1 , Elnaz Menhaji-Klotz 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-10-30 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01028 Markus Boehm 1 , Kevin Beaumont 1 , Rhys Jones 1 , Amit S. Kalgutkar 1 , Liying Zhang 1 , Karen Atkinson 2 , Guoyun Bai 2 , Janice A. Brown 2 , Heather Eng 2 , Gilles H. Goetz 2 , Brian R. Holder 2 , Bhagyashree Khunte 2 , Sarah Lazzaro 2 , Chris Limberakis 2 , Sangwoo Ryu 2 , Michael J. Shapiro 2 , Laurie Tylaska 2 , Jiangli Yan 2 , Rushia Turner 3 , Siegfried S. F. Leung 4, 5 , Mahesh Ramaseshan 5 , David A. Price 1 , Spiros Liras 1 , Matthew P. Jacobson 4 , David J. Earp 5 , R. Scott Lokey 3 , Alan M. Mathiowetz 1 , Elnaz Menhaji-Klotz 1
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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 (Ki < 100 nM) and measurable passive permeability (Papp > 5 × 10–6 cm/s). Moreover, bioactive peptide 25 (Ki = 9 nM) achieved oral bioavailability of 18% in rats, which was commensurate with the observed plasma clearance values upon intravenous administration.
中文翻译：
发现有效的和口服可利用的大环肽-类肽杂合CXCR7调节剂
趋化因子受体CXCR7是多种疾病的诱人靶标。尽管已经报道了CXCR7的几种小分子调节剂，但肽类大环化合物可能在效力，选择性和降低脱靶活性方面提供优势。我们生产了一系列肽类大环化合物，这些肽类大环化合物结合了N-连接的类肽功能性，其中类肽基团使我们能够探索远远超过天然氨基酸的侧链多样性。同时，理论计算和实验分析被用来跟踪和减少极性，同时密切监测理化性质。这种策略导致发现了具有高CXCR7结合亲和力（K i <100 nM）和可测量的被动渗透率（Papp > 5×10 –6 cm / s）。此外，生物活性肽25（K i = 9 nM）在大鼠中达到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相当。
更新日期：2017-10-30
中文翻译：
发现有效的和口服可利用的大环肽-类肽杂合CXCR7调节剂
趋化因子受体CXCR7是多种疾病的诱人靶标。尽管已经报道了CXCR7的几种小分子调节剂，但肽类大环化合物可能在效力，选择性和降低脱靶活性方面提供优势。我们生产了一系列肽类大环化合物，这些肽类大环化合物结合了N-连接的类肽功能性，其中类肽基团使我们能够探索远远超过天然氨基酸的侧链多样性。同时，理论计算和实验分析被用来跟踪和减少极性，同时密切监测理化性质。这种策略导致发现了具有高CXCR7结合亲和力（K i <100 nM）和可测量的被动渗透率（Papp > 5×10 –6 cm / s）。此外，生物活性肽25（K i = 9 nM）在大鼠中达到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相当。
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