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.
Yong-Jin Wu  1 ,  Jason Guernon  1 ,  Fukang Yang  1 ,  Lawrence Snyder  1 ,  Jianliang Shi  1 ,  Andrea Mcclure  1 ,  Ramkumar Rajamani  1 ,  Hyunsoo Park  1 ,  Alicia Ng  1 ,  Hal Lewis  2 ,  ChiehYing Chang  2 ,  Dan Camac  2 ,  Jeremy H Toyn  1 ,  Michael K Ahlijanian  1 ,  Charles F Albright  1 ,  John E Macor  2 ,  Lorin A Thompson  1
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.
PMID: 26985314 DOI: 10.1021/acsmedchemlett.5b00432
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.