Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I)

Sarwat Chowdhury; E. Hampton Sessions; Jennifer R Pocas; Wayne Grant; Thomas Schröter; Li Lin; Claudia Ruiz; Michael D Cameron; Stephan Schürer; Philip LoGrasso; Thomas D Bannister; Yangbo Feng

doi:10.1016/j.bmcl.2011.09.083

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Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I)

Journal article

Peer reviewed

Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I)

Sarwat Chowdhury, E. Hampton Sessions, Jennifer R Pocas, Wayne Grant, Thomas Schröter, Li Lin, Claudia Ruiz, Michael D Cameron, Stephan Schürer, Philip LoGrasso, …

Bioorganic & medicinal chemistry letters, Vol.21(23), pp.7107-7112

2011

DOI: https://doi.org/10.1016/j.bmcl.2011.09.083

PMID: 22004718

Abstract

Protein kinase A

ROCK inhibitor

Rho kinase

Indole

Pyrazole

Azaindole

Rho kinase (ROCK) inhibitors are potential therapeutic agents to treat disorders such as hypertension, multiple sclerosis, cancers, and glaucoma. Here, we disclose the synthesis, optimization, biological evaluation of potent indole and 7-azaindole based ROCK inhibitors that have high potency on ROCK (IC 50 = 1 nM) with 740-fold selectivity over PKA ( 47). Moreover, 47 showed very good DMPK properties making it a good candidate for further development. Finally, docking studies with a homology model of ROCK-II were performed to rationalize the binding mode of these compounds and showed the compounds bound in both orientations to take advantage to H-bonds with Lys-121 of ROCK-II.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.96 Cell Biology; 1.96.224 Integrins
Web Of Science research areas: Chemistry, Medicinal; Chemistry, Organic
ESI research areas: Chemistry

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Details

Title: Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I)
Creators: Sarwat Chowdhury - Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #2A1, Jupiter, FL 33458, USA
E. Hampton Sessions - Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #2A1, Jupiter, FL 33458, USA
Jennifer R Pocas - Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #2A1, Jupiter, FL 33458, USA
Wayne Grant - Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #2A1, Jupiter, FL 33458, USA
Thomas Schröter - Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #2A1, Jupiter, FL 33458, USA
Li Lin - Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #2A1, Jupiter, FL 33458, USA
Claudia Ruiz - Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #2A1, Jupiter, FL 33458, USA
Michael D Cameron - Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #2A1, Jupiter, FL 33458, USA
Stephan Schürer - Department of Pharmacology and Center for Computational Science, University of Miami, Miami, FL 33136, USA
Philip LoGrasso - Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #2A1, Jupiter, FL 33458, USA
Thomas D Bannister - Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #2A1, Jupiter, FL 33458, USA
Yangbo Feng - Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #2A1, Jupiter, FL 33458, USA
Publication Details: Bioorganic & medicinal chemistry letters, Vol.21(23), pp.7107-7112
Publisher: Elsevier Ltd
Academic Unit: Miller School of Medicine; Molecular and Cellular Pharmacology Research
Language: English
Resource Type: Journal article
PMID: 22004718
Record Identifier: 991031559104802976