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Quantifying Agonist Activity at G Protein-coupled Receptors
Published on: December 26, 2011
Functionalized 6-(Piperidin-1-yl)-8,9-Diphenyl Purines as Peripherally Restricted Inverse Agonists of the CB1
George Amato1, Amruta Manke1, Robert Wiethe1
1Discovery Science and Technology , RTI International , 3040 Cornwallis Road , Research Triangle Park , North Carolina 27709-2194 , United States.
Abstract:
Peripherally restricted CB1 receptor antagonists may be useful in treating metabolic syndrome, diabetes, liver diseases, and gastrointestinal disorders. Clinical development of the centrally acting CB1 inverse agonist otenabant (1) was halted due to its potential of producing adverse effects. SAR studies of 1 are reported herein with the objective of producing peripherally restricted analogues. Crystal structures of hCB1 and docking studies with 1 indicate that the piperidine group could be functionalized at the 4-position to access a binding pocket that can accommodate both polar and nonpolar groups. The piperidine is studied as a linker, functionalized with alkyl, heteroalkyl, aryl, and heteroaryl groups using a urea connector. Orally bioavailable and peripherally selective compounds have been produced that are potent inverse agonists of hCB1 with exceptional selectivity for hCB1 over hCB2. Compound 38 blocked alcohol-induced liver steatosis in mice and has good ADME properties for further development.
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