Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

Yong-Jin Wu; Jason Guernon; Fukang Yang; Lawrence Snyder; Jianliang Shi; Andrea Mcclure; Ramkumar Rajamani; Hyunsoo Park; Alicia Ng; Hal Lewis; ChiehYing Chang; Dan Camac; Jeremy H Toyn; Michael K Ahlijanian; Charles F Albright; John E Macor; Lorin A Thompson

doi:10.1021/acsmedchemlett.5b00432

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

ACS Med Chem Lett. 2016 Jan 11;7(3):271-6. doi: 10.1021/acsmedchemlett.5b00432. eCollection 2016 Mar 10.

Authors

Yong-Jin Wu¹, Jason Guernon¹, Fukang Yang¹, Lawrence Snyder¹, Jianliang Shi¹, Andrea Mcclure¹, Ramkumar Rajamani¹, Hyunsoo Park¹, Alicia Ng¹, Hal Lewis², ChiehYing Chang², Dan Camac², Jeremy H Toyn¹, Michael K Ahlijanian¹, Charles F Albright¹, John E Macor², Lorin A Thompson¹

Affiliations

¹ Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
² Research and Development, Bristol-Myers Squibb Company , PO Box 4000, Princeton, New Jersey 08543-4000, United States.

Abstract

By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose-response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease.

Keywords: Alzheimer’s disease; Aβ42; BACE1; aminothiazine; amyloid hypothesis; inhibitor.