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

Abstract

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.

• Authors: Dinesh A Barawkar, Ashwin Meru, Anish Bandyopadhyay, Abir Banerjee, Anil M Deshpande, Chandrashekhar Athare, Chandrasekhar Koduru, Goraksha Khose, Jayasagar Gundu, Koshu Mahajan, Pradeep Patil, Sachin R Kandalkar, Sanjay Niranjan, Shubhangi Bhosale, Siddhartha De, Sudit Mukhopadhyay, Sumit Chaudhary, Summon Koul, Umesh Singh, Anita Chugh, Venkata P Palle, Kasim A Mookhtiar, Joseph Vacca, Prasun K Chakravarty, Ravi P Nargund, Samuel D Wright, Sophie Roy, Michael P Graziano, Sheo B Singh, Doris Cully, Tian-Quan Cai
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 2 Issue 12 Pg. 919-23 (Dec 08 2011) ISSN: 1948-5875 [Print] United States
• PMID: 24900281 (Publication Type: Journal Article)