title: Discovery of a potent and selective small molecule hGPR91 antagonist.
abstract: GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 μM)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5 g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; >100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; >100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay.
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics, Quantum Towers, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune, India. debnath.b@advinus.com
authors.forename: Debnath
authors.initials: D
authors.lastname: Bhuniya
authors.forename: Dhananjay
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authors.lastname: Umrani
authors.forename: Bhavesh
authors.initials: B
authors.lastname: Dave
authors.forename: Deepak
authors.initials: D
authors.lastname: Salunke
authors.forename: Gagan
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authors.lastname: Kukreja
authors.forename: Jayasagar
authors.initials: J
authors.lastname: Gundu
authors.forename: Minakshi
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authors.lastname: Naykodi
authors.forename: Nadim S
authors.initials: NS
authors.lastname: Shaikh
authors.forename: Prasad
authors.initials: P
authors.lastname: Shitole
authors.forename: Santosh
authors.initials: S
authors.lastname: Kurhade
authors.forename: Siddhartha
authors.initials: S
authors.lastname: De
authors.forename: Sreemita
authors.initials: S
authors.lastname: Majumdar
authors.forename: Srinivasa B
authors.initials: SB
authors.lastname: Reddy
authors.forename: Suhas
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authors.lastname: Tambe
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Shejul
authors.forename: Anita
authors.initials: A
authors.lastname: Chugh
authors.forename: Venkata P
authors.initials: VP
authors.lastname: Palle
authors.forename: Kasim A
authors.initials: KA
authors.lastname: Mookhtiar
authors.forename: Doris
authors.initials: D
authors.lastname: Cully
authors.forename: Joseph
authors.initials: J
authors.lastname: Vacca
authors.forename: Prasun K
authors.initials: PK
authors.lastname: Chakravarty
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Nargund
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
authors.forename: Michael P
authors.initials: MP
authors.lastname: Graziano
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.forename: Sophie
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authors.lastname: Roy
authors.forename: Tian-Quan
authors.initials: TQ
authors.lastname: Cai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D055808:Drug Discovery; D020128:Inhibitory Concentration 50; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries