Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain l-2-hydroxy acid oxidase
| Autor: | Mahesh Kumar Mone, Summon Koul, Sophie Roy, Anil M. Deshpande, Sachin Kandalkar, Ravi P. Nargund, Jayasagar Gundu, Anita Chugh, Michael P. Graziano, Doris F. Cully, Tian-Quan Cai, Prasun K. Chakravarty, Samir Vyas, Sheo B. Singh, Joseph P. Vacca, Umesh Prasad Singh, Pradeep Rangrao Patil, Ashwin Meru, Dinesh A. Barawkar, Goraksha Khose, Shubhangi Bhosale, Anish Bandyopadhyay, Venkata P. Palle, Kasim A. Mookhtiar, Samuel D. Wright, Siddhartha De |
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| Rok vydání: | 2012 |
| Předmět: |
Candidate gene
Stereochemistry Carboxylic acid Clinical Biochemistry Carboxylic Acids Drug Evaluation Preclinical Pharmaceutical Science Thiophenes Pyrazole Kidney Biochemistry Gene product Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Animals Humans Structure–activity relationship Computer Simulation Enzyme Inhibitors Binding site Molecular Biology chemistry.chemical_classification Oxidase test Binding Sites Organic Chemistry Kidney metabolism Protein Structure Tertiary Rats Alcohol Oxidoreductases Liver chemistry Pyrazoles Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:4341-4347 |
| ISSN: | 0960-894X |
| Popis: | Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2. |
| Databáze: | OpenAIRE |
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