| Literature DB >> 24900281 |
Dinesh A Barawkar1, Ashwin Meru1, Anish Bandyopadhyay1, Abir Banerjee1, Anil M Deshpande1, Chandrashekhar Athare1, Chandrasekhar Koduru1, Goraksha Khose1, Jayasagar Gundu1, Koshu Mahajan1, Pradeep Patil1, Sachin R Kandalkar1, Sanjay Niranjan1, Shubhangi Bhosale1, Siddhartha De1, Sudit Mukhopadhyay1, Sumit Chaudhary1, Summon Koul1, Umesh Singh1, Anita Chugh1, Venkata P Palle1, Kasim A Mookhtiar1, Joseph Vacca2, Prasun K Chakravarty2, Ravi P Nargund2, Samuel D Wright2, Sophie Roy2, Michael P Graziano2, Sheo B Singh2, Doris Cully2, Tian-Quan Cai2.
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.Entities:
Keywords: DOCA rat; Hao2; hypertension; pyrazolecarboxylic acid
Year: 2011 PMID： 24900281 PMCID： PMC4018152 DOI： 10.1021/ml2001938
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345