Potent and Selective Inhibitors of Long Chain l-2-Hydroxy Acid Oxidase Reduced Blood Pressure in DOCA Salt-Treated Rats

• Published in: ACS medicinal chemistry letters Vol. 2; no. 12; pp. 919 - 923
• Main Authors: Barawkar, Dinesh A, Meru, Ashwin, Bandyopadhyay, Anish, Banerjee, Abir, Deshpande, Anil M, Athare, Chandrashekhar, Koduru, Chandrasekhar, Khose, Goraksha, Gundu, Jayasagar, Mahajan, Koshu, Patil, Pradeep, Kandalkar, Sachin R, Niranjan, Sanjay, Bhosale, Shubhangi, De, Siddhartha, Mukhopadhyay, Sudit, Chaudhary, Sumit, Koul, Summon, Singh, Umesh, Chugh, Anita, Palle, Venkata P, Mookhtiar, Kasim A, Vacca, Joseph, Chakravarty, Prasun K, Nargund, Ravi P, Wright, Samuel D, Roy, Sophie, Graziano, Michael P, Singh, Sheo B, Cully, Doris, Cai, Tian-Quan
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08-12-2011
• Subjects: Letter; pyrazolecarboxylic acid; DOCA rat; hypertension; Hao2
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml2001938

l-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits 1 and 2 led to the discovery of compounds 3 and 4 as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitable for in vivo studies in rats. Treatment with compound 3 or 4 resulted in a significant reduction or attenuation of blood pressure in an established or developing model of hypertension, deoxycorticosterone acetate-treated rats. This is the first report demonstrating a pharmacological benefit of selective Hao2 inhibitors in a relevant model of hypertension.