An asymmetric synthesis of the major metabolite of the calcitonin gene-related peptide recepotor antagonist BMS-846372 is presented. The variously substituted cyclohepta[b]pyridine ring system represents an underexplored ring system and showed some unexpected chemistry. Reactivities of epoxide and ketone functional groups on the cycloheptane ring were extensively controlled by a remote bulky TIPS group. The rate difference of the hydrogenolysis between two diastereomeric epoxide intermediates shed some light on the mechanism of epoxide hydrogenolysis, and further, deuterium labeling studies revealed more mechanistic details on this well-known chemical transformation for the first time.

21 Sep 2012·Organic lettersQ1 · CHEMISTRY

Efficient and Scalable Enantioselective Synthesis of a CGRP Antagonist

Q1 · CHEMISTRY

Article

Author: Chen, Ling ; Luo, Guanglin ; Leahy, David K. ; Zhu, Jason ; Cuniere, Nicolas ; Hanson, Ronald L. ; Guo, Zhiwei ; Fan, Yu ; Chan, Collin ; Hsiao, Yi ; Gao, Qi ; Desai, Lopa V. ; Sugiyama, Masano ; Rosner, Thorsten

An enantioselective synthesis of the CGRP antagonist BMS-846372, amenable to large scale preparation, is presented. This new synthesis showcases a chemo- and enantioselective reduction of a cyclohepta[b]pyridine-5,9-dione as well as a Pd-catalyzed alpha-arylation reaction to form the key carbon-carbon bond and set the absolute and relative stereochemistry.

12 Apr 2012·ACS medicinal chemistry lettersQ3 · MEDICINE

Discovery of BMS-846372, a Potent and Orally Active Human CGRP Receptor Antagonist for the Treatment of Migraine

Q3 · MEDICINE

Article

Author: Huang, Yanling ; Macor, John E. ; Luo, Guanglin ; Denton, Rex ; Kostich, Walter ; Chen, Ling ; Lentz, Kimberley A. ; Signor, Laura ; Dubowchik, Gene M. ; Schartman, Richard ; Conway, Charles M. ; Browning, Marc ; Keavy, Deborah ; Gulianello, Michael ; Mercer, Stephen E.

Calcitonin gene-related peptide (CGRP) receptor antagonists have been clinically shown to be effective in the treatment of migraine, but identification of potent and orally bioavailable compounds has been challenging. Herein, we describe the conceptualization, synthesis, and preclinical characterization of a potent, orally active CGRP receptor antagonist 5 (BMS-846372). Compound 5 has good oral bioavailability in rat, dog, and cynomolgus monkeys and overall attractive preclinical properties including strong (>50% inhibition) exposure-dependent in vivo efficacy in a marmoset migraine model.

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Indication	Highest Phase	Country/Location	Organization	Date
Migraine Disorders	Preclinical	United States	Bristol Myers Squibb Co.	08 Mar 2012

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