title: 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.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Dinesh A
authors.initials: DA
authors.lastname: Barawkar
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Ashwin
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authors.lastname: Meru
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Anish
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authors.lastname: Bandyopadhyay
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Abir
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authors.lastname: Banerjee
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
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authors.initials: AM
authors.lastname: Deshpande
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Chandrashekhar
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authors.lastname: Athare
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
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authors.initials: C
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authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
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authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
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authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
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authors.lastname: Mahajan
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Pradeep
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authors.lastname: Patil
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Sachin R
authors.initials: SR
authors.lastname: Kandalkar
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
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authors.lastname: Niranjan
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Shubhangi
authors.initials: S
authors.lastname: Bhosale
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: De
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Sudit
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authors.lastname: Mukhopadhyay
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Sumit
authors.initials: S
authors.lastname: Chaudhary
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Summon
authors.initials: S
authors.lastname: Koul
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Umesh
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authors.lastname: Singh
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Anita
authors.initials: A
authors.lastname: Chugh
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Venkata P
authors.initials: VP
authors.lastname: Palle
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Limited , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Kasim A
authors.initials: KA
authors.lastname: Mookhtiar
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Vacca
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Prasun K
authors.initials: PK
authors.lastname: Chakravarty
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Nargund
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Graziano
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Doris
authors.initials: D
authors.lastname: Cully
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Tian-Quan
authors.initials: TQ
authors.lastname: Cai
keywords: DOCA rat; Hao2; hypertension; pyrazolecarboxylic acid