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.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
Bhuniya D,Umrani D,Dave B,Salunke D,Kukreja G,Gundu J,Naykodi M,Shaikh NS,Shitole P,Kurhade S,De S,Majumdar S,Reddy SB,Tambe S,Shejul Y,Chugh A,Palle VP,Mookhtiar KA,Cully D,Vacca J,Chakravarty PK,Nargund RP,Wdoi
10.1016/j.bmcl.2011.04.091subject
Has Abstractpub_date
2011-06-15 00:00:00pages
3596-602issue
12eissn
0960-894Xissn
1464-3405pii
S0960-894X(11)00561-0journal_volume
21pub_type
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