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

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.