Hit-to-lead optimization and discovery of a potent, and orally bioavailable G protein coupled receptor kinase 2 (GRK2) inhibitor.

Bioorganic & medicinal chemistry letters 2020 Dec 01

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G-protein coupled receptor kinase 2 (GRK2), which is upregulated in the failing heart, appears to play a critical role in heart failure (HF) progression in part because enhanced GRK2 activity promotes dysfunction of β-adrenergic signaling and myocyte death. An orally bioavailable GRK2 inhibitor could offer unique therapeutic outcomes that cannot be attained by current heart failure treatments that directly target GPCRs or angiotensin-converting enzyme. Herein, we describe the discovery of a potent, selective, and orally bioavailable GRK2 inhibitor, 8h, through high-throughput screening, hit-to-lead optimization, structure-based design, molecular modelling, synthesis, and biological evaluation. In the cellular target engagement assays, 8h enhances isoproterenol-mediated cyclic adenosine 3',5'-monophosphate (cAMP) production in HEK293 cells overexpressing GRK2. Compound 8h was further evaluated in a human stem cell-derived cardiomyocyte (HSC-CM) contractility assay and potentiated isoproterenol-induced beating rate in HSC-CMs. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Guozhang Xu, Michael D Gaul, Zhijie Liu, Renee L DesJarlais, Jenson Qi, Weixue Wang, Daniel Krosky, Ioanna Petrounia, Cynthia M Milligan, An Hermans, Hua-Rong Lu, Devine Zheng Huang, June Zhi Xu, John C Spurlino. Hit-to-lead optimization and discovery of a potent, and orally bioavailable G protein coupled receptor kinase 2 (GRK2) inhibitor. Bioorganic & medicinal chemistry letters. 2020 Dec 01;30(23):127602