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

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

Modulators of CXCR4 and CXCR7/ACKR3 Function

“…5), with equal high-affinity agonism on human (13 nM) and mouse (51 nM) ACKR3. In vivo tests showed reduction of cardiac fibrosis in a mouse model (Menhaji-Klotz et al, 2018). A range of pharmacological data in this study can facilitate the use of this ligand to study ACKR3.…”

Stimulation of the atypical chemokine receptor 3 (ACKR3) by a small-molecule agonist attenuates fibrosis in a preclinical liver but not lung injury model

“…The ACKR3 agonist (compound 18 from [ 21 ]) was custom synthesized by Aragen Life Sciences Pvt. Ltd. (India) according to the previously described procedure [ 21 ], commissioned by the Centre for Drug Design and Discovery (CD3). The ALK5/ALK4 kinase inhibitor SM 16 [ 22 ] was purchased from ChemScene (CS-0042167).…”

“…In this model, the ACKR3 agonist blocked the CXCL12-scavenging function of ACKR3, which led to increased CXCL12 plasma levels. It was further suggested that cardiac function improved due to enhanced CXCR4 activity [ 21 ].…”

“…In this study we further embarked on the potential anti-fibrotic role of ACKR3 agonism by studying the effect of this previously described ACKR3-targeting small molecule agonist [ 21 ] in preclinical mouse models of lung and liver fibrosis. The ACKR3 agonist was resynthesized and its in vitro pharmacological properties were studied to confirm receptor potency, efficacy and specificity.…”

Advances in CXCR7 Modulators

“…A 1,4-diazepene agonist was discovered with low nM potency, but it is lipophilic and inhibits hERG [81]. After performing SAR, a tertiary β-amino amide ( Figure 2) was developed [82]. This compound has similar affinity for CXCR7 (a K i of 13 nM and an EC 50 of 11 nM for β-arrestin recruitment), and a larger therapeutic window for hERG.…”