Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481

Kenneth M Boy; Jason M Guernon; Dmitry S Zuev; Li Xu; Yunhui Zhang; Jianliang Shi; Lawrence R Marcin; Mendi A Higgins; Yong-Jin Wu; Subramaniam Krishnananthan; Jianqing Li; Ashok Trehan; Daniel Smith; Jeremy H Toyn; Jere E Meredith; Catherine R Burton; S Roy Kimura; Tatyana Zvyaga; Xiaoliang Zhuo; Kimberley A Lentz; James E Grace; Rex Denton; John S Morrison; Arvind Mathur; Charles F Albright; Michael K Ahlijanian; Richard E Olson; Lorin A Thompson; John E Macor

doi:10.1021/acsmedchemlett.8b00541

Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481

ACS Med Chem Lett. 2019 Feb 17;10(3):312-317. doi: 10.1021/acsmedchemlett.8b00541. eCollection 2019 Mar 14.

Authors

Kenneth M Boy¹, Jason M Guernon¹, Dmitry S Zuev¹, Li Xu¹, Yunhui Zhang¹, Jianliang Shi¹, Lawrence R Marcin¹, Mendi A Higgins¹, Yong-Jin Wu¹, Subramaniam Krishnananthan¹, Jianqing Li¹, Ashok Trehan¹, Daniel Smith¹, Jeremy H Toyn¹, Jere E Meredith¹, Catherine R Burton¹, S Roy Kimura¹, Tatyana Zvyaga¹, Xiaoliang Zhuo¹, Kimberley A Lentz¹, James E Grace¹, Rex Denton¹, John S Morrison¹, Arvind Mathur², Charles F Albright¹, Michael K Ahlijanian¹, Richard E Olson¹, Lorin A Thompson¹, John E Macor¹

Affiliations

¹ Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States.
² Bristol-Myers Squibb, Princeton, New Jersey 08543, United States.

Abstract

A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce the bicyclic pyrimidine γ-secretase modulator BMS-932481. The compound showed robust reductions of Aβ_1-42 and Aβ_1-40 in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-secretase modulator mechanism, increases in Aβ_1-37 and Aβ_1-38 were observed, with no change in the total amount of Aβ_1-x produced. No Notch-based toxicity was observed, and the overall preclinical profile of BMS-932481 supported its further evaluation in human clinical trials.