2. Academic Validation
  3. Discovery of a potent and selective small molecule hGPR91 antagonist

Discovery of a potent and selective small molecule hGPR91 antagonist

  • Bioorg Med Chem Lett. 2011 Jun 15;21(12):3596-602. doi: 10.1016/j.bmcl.2011.04.091.
Debnath Bhuniya 1,  Dhananjay Umrani,  Bhavesh Dave,  Deepak Salunke,  Gagan Kukreja,  Jayasagar Gundu,  Minakshi Naykodi,  Nadim S Shaikh,  Prasad Shitole,  Santosh Kurhade,  Siddhartha De,  Sreemita Majumdar,  Srinivasa B Reddy,  Suhas Tambe,  Yogesh Shejul,  Anita Chugh,  Venkata P Palle,  Kasim A Mookhtiar,  Doris Cully,  Joseph Vacca,  Prasun K Chakravarty,  Ravi P Nargund,  Samuel D Wright,  Michael P Graziano,  Sheo B Singh,  Sophie Roy,  Tian-Quan Cai
Affiliations

Affiliation

  • 1 Drug Discovery Facility, Advinus Therapeutics, Quantum Towers, Rajiv Gandhi InfoTech Park, Hinjewadi, Pune, India. [email protected]
PMID: 21571530 DOI: 10.1016/j.bmcl.2011.04.091
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.

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