2. Academic Validation
  3. Discovery of a Novel Small-Molecule Modulator of C-X-C Chemokine Receptor Type 7 as a Treatment for Cardiac Fibrosis

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

Affiliations

  • 1 Pfizer Worldwide Research & Development , Cambridge , Massachusetts 02139 , United States.
  • 2 Pfizer Worldwide Research & Development , Groton , Connecticut 06340 , United States.
PMID: 29627981 DOI: 10.1021/acs.jmedchem.8b00190
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.

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