Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain l-2-hydroxy acid oxidase
2012
Barawkar, Dinesh A. | Bandyopadhyay, Anish | Deshpande, Anil | Koul, Summon | Kandalkar, Sachin | Patil, Pradeep | Khose, Goraksha | Vyas, Samir | Mone, Mahesh | Bhosale, Shubhangi | Singh, Umesh | De, Siddhartha | Meru, Ashwin | Gundu, Jayasagar | Chugh, Anita | Palle, Venkata P. | Mookhtiar, Kasim A. | Vacca, Joseph P. | Chakravarty, Prasun K. | Nargund, Ravi P. | Wright, Uel | Roy, Sophie | Graziano, Michael P. | Cully, Doris | Cai, Tian-Quan | Singh, Sheo B.
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.
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