Journal of Medicinal Chemistry p. 5564 - 5567 (2007)
Update date:2022-08-03
Topics: Antagonists Discovery Potent Orally bioavailable 2,2,2-trifluoroethyl
Paone, Daniel V.
Shaw, Anthony W.
Nguyen, Diem N.
Burgey, Christopher S.
Deng, James Z.
Kane, Stefanie A.
Koblan, Kenneth S.
Salvatore, Christopher A.
Mosser, Scott D.
Johnston, Victor K.
Wong, Bradley K.
Miller-Stein, Cynthia M.
Hershey, James C.
Graham, Samuel L.
Vacca, Joseph P.
Williams, Theresa M.
Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Herein we describe optimization of CGRP receptor antagonists based on an earlier lead structure containing a (3R)-amino-(6S)- phenylcaprolactam core. Replacement of the phenylimidazolinone with an azabenzimidazolone gave stable derivatives with lowered serum shifts. Extensive SAR studies of the C-6 aryl moiety revealed the potency-enhancing effect of the 2,3-difluorophenyl group, and trifluoroethylation of the N-1 amide position resulted in improved oral bioavailabilities, ultimately leading to clinical candidate 38 (MK-0974).
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