Discovery of a Novel Small-Molecule Modulator of C–X–C Chemokine Receptor Type 7 as a Treatment for Cardiac Fibrosis

Elnaz Menhaji-Klotz, Kevin D. Hesp, Allyn T. Londregan, Amit S. Kalgutkar, David W. Piotrowski, Markus Boehm, Kun Song, Tim Ryder, Kevin Beaumont, Rhys M. Jones, Karen Atkinson, Janice A. Brown, John Litchfield, Jun Xiao, Daniel P. Canterbury, Kristen Burford, Benjamin A. Thuma, Chris Limberakis, Wenhua Jiao, Scott W. Bagley, Saket Agarwal, Danielle Crowell, Stephen Pazdziorko, Jessica Ward, David A. Price, Valerie Clerin

Index: 10.1021/acs.jmedchem.8b00190

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Abstract

C–X–C chemokine receptor type 7 (CXCR7) is involved in cardiac and immune pathophysiology. We report the discovery of a novel 1,4-diazepine CXCR7 modulator, demonstrating for the first time the role of pharmacological CXCR7 intervention in cardiac repair. Structure–activity-relationship (SAR) studies demonstrated that a net reduction in lipophilicity (log D) and an incorporation of saturated ring systems yielded compounds with good CXCR7 potencies and improvements in oxidative metabolic stability in human-liver microsomes (HLM). Tethering an ethylene amide further improved the selectivity profile (e.g., for compound 18, CXCR7 Ki = 13 nM, adrenergic α 1a Kb > 10 000 nM, and adrenergic β 2 Kb > 10 000 nM). The subcutaneous administration of 18 in mice led to a statistically significant increase in circulating concentrations of plasma stromal-cell-derived factor 1α (SDF-1α) of approximately 2-fold. Chronic dosing of compound 18 in a mouse model of isoproterenol-induced cardiac injury further resulted in a statistically significant reduction of cardiac fibrosis.