Identification of potent, highly constrained CGRP receptor antagonists

…, JC Hershey, R Jelley, C Kreatsoulas, EL Moore…

Index: Stump, Craig A.; Bell, Ian M.; Bednar, Rodney A.; Fay, John F.; Gallicchio, Steven N.; Hershey, James C.; Jelley, Richard; Kreatsoulas, Constantine; Moore, Eric L.; Mosser, Scott D.; Quigley, Amy G.; Roller, Shane A.; Salvatore, Christopher A.; Sharik, Steven S.; Theberge, Cory R.; Zartman, C. Blair; Kane, Stefanie A.; Graham, Samuel L.; Selnick, Harold G.; Vacca, Joseph P.; Williams, Theresa M. Bioorganic and Medicinal Chemistry Letters, 2010 , vol. 20, # 8 p. 2572 - 2576

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Citation Number: 5

Abstract

A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP Ki= 23pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP Ki= 0.52 nM) and displayed a good ...