Discovery of a Novel Small-Molecule Modulator of C-X-C Chemokine Receptor Type 7 as a Treatment for Cardiac Fibrosis PMID: 29627981

Target-related Cytokines

2026-09-23

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

J Med Chem. 2018 Apr 26;61(8):3685-3696. doi: 10.1021/acs.jmedchem.8b00190.

Elnaz Menhaji-Klotz ¹ , Kevin D Hesp ² , Allyn T Londregan ² , Amit S Kalgutkar ¹ , David W Piotrowski ² , Markus Boehm ¹ , Kun Song ¹ , Tim Ryder ² , Kevin Beaumont ¹ , Rhys M Jones ¹ , Karen Atkinson ² , Janice A Brown ² , John Litchfield ¹ , Jun Xiao ² , Daniel P Canterbury ² , Kristen Burford ² , Benjamin A Thuma ² , Chris Limberakis ² , Wenhua Jiao ² , Scott W Bagley ² , Saket Agarwal ¹ , Danielle Crowell ¹ , Stephen Pazdziorko ¹ , Jessica Ward ¹ , David A Price ¹ , Valerie Clerin ¹

Affiliations

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 K_i = 13 nM, adrenergic α 1a K_b > 10 000 nM, and adrenergic β 2 K_b > 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.