Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine.
In heart failure, the β-adrenergic receptors (βARs) become desensitized and uncoupled from heterotrimeric G proteins. This process is initiated by G protein-coupled receptor kinases (GRKs), some of which are upregulated in the failing heart, making them desirable therapeutic targets. The selective serotonin reuptake inhibitor, paroxetine, was previously identified as a GRK2 inhibitor. Utilizing a structure-based drug design approach, we modified paroxetine to generate a small compound library. Included in this series is a highly potent and selective GRK2 inhibitor, 14as, with an IC50of 30 nM against GRK2 and greater than 230-fold selectivity over other GRKs and kinases. Furthermore, 14as showed a 100-fold improvement in cardiomyocyte contractility assays over paroxetine and a plasma concentration higher than its IC50for over 7 h. Three of these inhibitors, including 14as, were additionally crystallized in complex with GRK2 to give insights into the structural determinants of potency and selectivity of these inhibitors.
Department of Medicinal Chemistry, College of Pharmacy, ‡Departments of Pharmacology and Biological Chemistry, Life Sciences Institute, §Ph.D. Program in Chemical Biology, ⊥Vahlteich Medicinal Chemistry Core, University of Michigan , Ann Arbor, Michigan 48109, United States.|Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
Helen V
HV
Waldschmidt
Department of Medicinal Chemistry, College of Pharmacy, ‡Departments of Pharmacology and Biological Chemistry, Life Sciences Institute, §Ph.D. Program in Chemical Biology, ⊥Vahlteich Medicinal Chemistry Core, University of Michigan , Ann Arbor, Michigan 48109, United States.|Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
Kristoff T
KT
Homan
Department of Medicinal Chemistry, College of Pharmacy, ‡Departments of Pharmacology and Biological Chemistry, Life Sciences Institute, §Ph.D. Program in Chemical Biology, ⊥Vahlteich Medicinal Chemistry Core, University of Michigan , Ann Arbor, Michigan 48109, United States.|Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
Marilyn C
MC
Cato
Department of Medicinal Chemistry, College of Pharmacy, ‡Departments of Pharmacology and Biological Chemistry, Life Sciences Institute, §Ph.D. Program in Chemical Biology, ⊥Vahlteich Medicinal Chemistry Core, University of Michigan , Ann Arbor, Michigan 48109, United States.|Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
Osvaldo
O
Cruz-Rodríguez
Department of Medicinal Chemistry, College of Pharmacy, ‡Departments of Pharmacology and Biological Chemistry, Life Sciences Institute, §Ph.D. Program in Chemical Biology, ⊥Vahlteich Medicinal Chemistry Core, University of Michigan , Ann Arbor, Michigan 48109, United States.|Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
Alessandro
A
Cannavo
Department of Medicinal Chemistry, College of Pharmacy, ‡Departments of Pharmacology and Biological Chemistry, Life Sciences Institute, §Ph.D. Program in Chemical Biology, ⊥Vahlteich Medicinal Chemistry Core, University of Michigan , Ann Arbor, Michigan 48109, United States.|Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
Michael W
MW
Wilson
Department of Medicinal Chemistry, College of Pharmacy, ‡Departments of Pharmacology and Biological Chemistry, Life Sciences Institute, §Ph.D. Program in Chemical Biology, ⊥Vahlteich Medicinal Chemistry Core, University of Michigan , Ann Arbor, Michigan 48109, United States.|Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
Jianliang
J
Song
Department of Medicinal Chemistry, College of Pharmacy, ‡Departments of Pharmacology and Biological Chemistry, Life Sciences Institute, §Ph.D. Program in Chemical Biology, ⊥Vahlteich Medicinal Chemistry Core, University of Michigan , Ann Arbor, Michigan 48109, United States.|Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
Joseph Y
JY
Cheung
Department of Medicinal Chemistry, College of Pharmacy, ‡Departments of Pharmacology and Biological Chemistry, Life Sciences Institute, §Ph.D. Program in Chemical Biology, ⊥Vahlteich Medicinal Chemistry Core, University of Michigan , Ann Arbor, Michigan 48109, United States.|Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
Walter J
WJ
Koch
Department of Medicinal Chemistry, College of Pharmacy, ‡Departments of Pharmacology and Biological Chemistry, Life Sciences Institute, §Ph.D. Program in Chemical Biology, ⊥Vahlteich Medicinal Chemistry Core, University of Michigan , Ann Arbor, Michigan 48109, United States.|Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
John J G
JJ
Tesmer
Department of Medicinal Chemistry, College of Pharmacy, ‡Departments of Pharmacology and Biological Chemistry, Life Sciences Institute, §Ph.D. Program in Chemical Biology, ⊥Vahlteich Medicinal Chemistry Core, University of Michigan , Ann Arbor, Michigan 48109, United States.|Center for Translational Medicine, Temple University , Philadelphia, Pennsylvania 19140, United States.
Scott D
0000-0001-8440-4990
SD
Larsen
D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D017374:Paroxetine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D017374:Paroxetine; D054769:G-Protein-Coupled Receptor Kinase 2