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).
View Morewebsite:http://www.synchemie.com/
Contact:+86-574-87642758
Address:Room 901, Yinyi Bund Building, 132 Renmin Road
Contact:+86-574-87065746
Address:10th Floor, No.787 Baizhang East Road,
Contact:0086 533 2282832
Address:Zibo,Shandong
KINHENG CHEMICAL(SHANGHAI)CO., LTD.
Contact:+8621-60490170
Address:Room401, No.28,Lane 189, Yangshupu Rd. Shanghai, China.
Fuxin Jintelai Fluorin Chemical Co., Ltd.
Contact:+86-0418-8229599
Address:, 7th Huagong Road, Fluorine industry development zone (Yimatu Town,Fumeng County),Fuxin City, Liaoning Province, China
Doi:10.1021/jm020210h
(2002)Doi:10.1021/ja01162a543
(1950)Doi:10.1016/S0968-0896(02)00108-6
(2002)Doi:10.1039/c5ra03255e
(2015)Doi:10.1021/ja01283a033
(1937)Doi:10.1021/ja00176a039
(1990)