Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain l-2-hydroxy acid oxidase

• Published in: Bioorganic & medicinal chemistry letters 2012-07, Vol.22 (13), p.4341-4347
• Main Authors: 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, Samuel D., Roy, Sophie, Graziano, Michael P., Cully, Doris, Cai, Tian-Quan, Singh, Sheo B.
• Format: Article
• Language: English
• Subjects: Alcohol Oxidoreductases - antagonists & inhibitors; Alcohol Oxidoreductases - metabolism; Animals; Binding Sites; Biological and medical sciences; Blood pressure; carboxylic acids; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacokinetics; Computer Simulation; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzymes; genes; Hao2; Humans; Hypertension; Inhibitor; Kidney; Kidney - enzymology; Kidney - metabolism; kidneys; Liver; Liver - enzymology; Liver - metabolism; Medical sciences; Pharmacology. Drug treatments; Protein Structure, Tertiary; Pyrazole carboxylic acid; pyrazoles; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - therapeutic use; Quantitative trait loci; Rats; screening; Structure-Activity Relationship; structure-activity relationships; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - therapeutic use
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.05.020

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.