Crowley, Brendan M.,Stump, Craig A.,Nguyen, Diem N.,Potteiger, Craig M.,McWherter, Melody A.,Paone, Daniel V.,Quigley, Amy G.,Bruno, Joseph G.,Cui, Dan,Culberson, J. Christopher,Danziger, Andrew,Fandozzi, Christine,Gauvreau, Danny,Kemmerer, Amanda L.,Menzel, Karsten,Moore, Eric L.,Mosser, Scott D.,Reddy, Vijay,White, Rebecca B.,Salvatore, Christopher A.,Kane, Stefanie A.,Bell, Ian M.,Selnick, Harold G.,Fraley, Mark E.,Burgey, Christopher S.

2015

November

Bioorganic & Medicinal Chemistry Lettersbioorganic & Medicinal Chemistry Letters

Novel oxazolidinone calcitonin gene-related peptide (CGRP) receptor antagonists for the acute treatment of migraine

Validated

()

25

2121

4777

4781

In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP + HS IC50 = 0.67 nM), and selective compound (hERG IC50 = 19 mu M) with favorable rodent pharmacokinetics (F = 100%, t(1/2) = 7 h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold). (C) 2015 Elsevier Ltd. All rights reserved.In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP + HS IC50 = 0.67 nM), and selective compound (hERG IC50 = 19 mu M) with favorable rodent pharmacokinetics (F = 100%, t(1/2) = 7 h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold). (C) 2015 Elsevier Ltd. All rights reserved.

0960-894X0960-894X

://WOS:000363275400015://WOS:000363275400015