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.
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In the presence of oxygen, conserved proline residues in HIF-1α are hydroxylated by PHD 1, 2 and 3, providing a recognition site for VHL E3 ubiquitin ligase, which ubiquitinates HIF-1α and targets it for proteasomal degradation.
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- Authors
- Bhuniya, D., Umrani, D., Dave, B., Salunke, D., Kukreja, G., Gundu, J., Naykodi, M., Shaikh, N. S., Shitole, P., Kurhade, S., De, S., Majumdar, S., Reddy, S. B., Tambe, S., Shejul, Y., Chugh, A., Palle, V. P., Mookhtiar, K. A., Cully, D., Vacca, J., Chakravarty, P. K., Nargund, R. P., Wright, S. D., Graziano, M. P., Singh, S. B., Roy, S., & Cai, T.-Q.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Bhuniya, Debnath
- ORCID
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 21
- Issue
- 12
- Pages
- 3596-3602
- ISSN
- 0960-894X (ISSN-L)
- OpenAlex
- W2139412340
- Cited by
- 80
- References
- 23
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 5 · 2020: 7 · 2019: 4 · 2018: 5 · 2017: 8 · 2016: 6 · 2015: 3 · 2013: 8 · 2012: 4
- FWCI
- 1.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Kementerian Pendidikan Nasional
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- GPR91, G protein-coupled receptor antagonists, succinic acid, structure-activity relationship, oral bioavailability, lead compound identification, pharmacodynamic assay, target engagement, renal hypertension, retinal angiogenesis, autoimmunity
- MeSH terms
- Administration, Oral, Animals, Male, Molecular Structure, Rats, Wistar, Inhibitory Concentration 50, Receptors, G-Protein-Coupled, Rats, Small Molecule Libraries, Drug Discovery
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