5UVC

Design, Synthesis, and Evaluation of the First Selective and Potent G-protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure

Summary for 5UVC

• Entry DOI: 10.2210/pdb5uvc/pdb
• Related: 5UUU
• Descriptor: Beta-adrenergic receptor kinase 1, N-benzyl-3-({[5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]methyl}amino)benzamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, heart failure, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P25098
• Total number of polymer chains: 1
• Total formula weight: 63812.66

Authors

Hoffman, I.D.,Lawson, J.D. (deposition date: 2017-02-20, release date: 2017-07-26, Last modification date: 2024-03-06)

Primary citation

Okawa, T.,Aramaki, Y.,Yamamoto, M.,Kobayashi, T.,Fukumoto, S.,Toyoda, Y.,Henta, T.,Hata, A.,Ikeda, S.,Kaneko, M.,Hoffman, I.D.,Sang, B.C.,Zou, H.,Kawamoto, T.
Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure.
J. Med. Chem., 60:6942-6990, 2017

PubMed Abstract: A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates β-adrenergic receptor (βAR)-mediated cAMP accumulation and prevents internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment.

PubMed: 28699740
DOI: 10.1021/acs.jmedchem.7b00443

Experimental method

X-RAY DIFFRACTION (2.65 Å)