Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain L-2-hydroxy acid oxidase.
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.
Drug Discovery Facility, Advinus Therapeutics, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India. dinesh.barawkar@advinus.com
Dinesh A
DA
Barawkar
Anish
A
Bandyopadhyay
Anil
A
Deshpande
Summon
S
Koul
Sachin
S
Kandalkar
Pradeep
P
Patil
Goraksha
G
Khose
Samir
S
Vyas
Mahesh
M
Mone
Shubhangi
S
Bhosale
Umesh
U
Singh
Siddhartha
S
De
Ashwin
A
Meru
Jayasagar
J
Gundu
Anita
A
Chugh
Venkata P
VP
Palle
Kasim A
KA
Mookhtiar
Joseph P
JP
Vacca
Prasun K
PK
Chakravarty
Ravi P
RP
Nargund
Samuel D
SD
Wright
Sophie
S
Roy
Michael P
MP
Graziano
Doris
D
Cully
Tian-Quan
TQ
Cai
Sheo B
SB
Singh
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use
D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D013876:Thiophenes; D000429:Alcohol Oxidoreductases; C500896:Hao2 protein, rat