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Discovery of a Novel Small-Molecule Modulator of C-X-C Chemokine Receptor Type 7 as a Treatment for Cardiac Fibrosis.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2018 Apr 26; Vol. 61 (8), pp. 3685-3696. Date of Electronic Publication: 2018 Apr 17. - Publication Year :
- 2018
-
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 <subscript>i</subscript> = 13 nM, adrenergic α 1a K <subscript>b</subscript> > 10 000 nM, and adrenergic β 2 K <subscript>b</subscript> > 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.
- Subjects :
- Acetamides chemical synthesis
Acetamides chemistry
Acetamides pharmacology
Animals
Azepines chemical synthesis
Azepines chemistry
Azepines pharmacology
Cardiotonic Agents chemical synthesis
Cardiotonic Agents chemistry
Cardiotonic Agents pharmacology
Dogs
Fibrosis chemically induced
Heart Diseases chemically induced
Humans
Hydrophobic and Hydrophilic Interactions
Isoproterenol
Madin Darby Canine Kidney Cells
Male
Mice, Inbred BALB C
Mice, Inbred C57BL
Microsomes, Liver metabolism
Molecular Structure
Structure-Activity Relationship
Acetamides therapeutic use
Azepines therapeutic use
Cardiotonic Agents therapeutic use
Fibrosis drug therapy
Heart Diseases drug therapy
Receptors, CXCR metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 61
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29627981
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.8b00190