Hit-to-lead optimization and discovery of a potent, and orally bioavailable G protein coupled receptor kinase 2 (GRK2) inhibitor. Issue 23 (1st December 2020)

• Record Type: Journal Article
• Authors: Xu, Guozhang; Gaul, Michael D.; Liu, Zhijie; DesJarlais, Renee L.; Qi, Jenson; Wang, Weixue; Krosky, Daniel; Petrounia, Ioanna; Milligan, Cynthia M.; Hermans, An; Lu, Hua-Rong; Huang, Devine Zheng; Xu, June Zhi; Spurlino, John C.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 23(2020)
• Publication Date: 2020-12-01
• Subjects: Heart failure -- β-Adrenergic receptor -- GRK2 inhibitor -- Cardiomyocytes -- Structure-based drug design -- Molecular modelling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127602
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.