Discovery of a Novel Small-Molecule Modulator of C-X-C Chemokine Receptor Type 7 as a Treatment for Cardiac Fibrosis
| Autor: | Kristen Burford, Daniel P. Canterbury, Wenhua Jiao, Kun Song, Saket Agarwal, Elnaz Menhaji-Klotz, Allyn T. Londregan, Karen Atkinson, Jun Xiao, Jessica Ward, John Litchfield, Kevin Beaumont, David W. Piotrowski, Janice A. Brown, Amit S. Kalgutkar, Danielle M. Crowell, Kevin D. Hesp, Tim F. Ryder, Scott W. Bagley, David Price, Stephen Pazdziorko, Benjamin A. Thuma, Markus Boehm, Valerie Clerin, Rhys M. Jones, Chris Limberakis |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Cardiotonic Agents Heart Diseases Cardiac fibrosis Adrenergic Pharmacology Madin Darby Canine Kidney Cells 03 medical and health sciences Chemokine receptor Structure-Activity Relationship 0302 clinical medicine Dogs Drug Discovery Acetamides medicine Structure–activity relationship Animals Humans Receptor Receptors CXCR Mice Inbred BALB C Molecular Structure Chemistry Isoproterenol Azepines medicine.disease Small molecule Fibrosis Mice Inbred C57BL 030104 developmental biology 030220 oncology & carcinogenesis Lipophilicity Microsome Microsomes Liver Molecular Medicine Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Journal of medicinal chemistry. 61(8) |
| ISSN: | 1520-4804 |
| Popis: | 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 st... |
| Databáze: | OpenAIRE |
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