Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints

  • Bioorg Med Chem. 2020 Jan 1;28(1):115194. doi: 10.1016/j.bmc.2019.115194.
Leonard L Winneroski  1 ,  Jon A Erickson  1 ,  Steven J Green  1 ,  Jose E Lopez  1 ,  Stephanie L Stout  1 ,  Warren J Porter ,  David E Timm ,  James E Audia  2 ,  Mario Barberis  1 ,  James P Beck  1 ,  Leonard N Boggs ,  Anthony R Borders  1 ,  Robert D Boyer  1 ,  Richard A Brier  1 ,  Erik J Hembre  1 ,  Jörg Hendle  3 ,  Pablo Garcia-Losada  1 ,  Jose Miguel Minguez  1 ,  Brian M Mathes  1 ,  Patrick C May ,  Scott A Monk  1 ,  Zoran Rankovic  4 ,  Yuan Shi  1 ,  Brian M Watson  1 ,  Zhixiang Yang  1 ,  Dustin J Mergott  5
Affiliations
  • 1. Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
  • 2. Constellation Pharmaceuticals, Cambridge, MA 02140, USA(2).
  • 3. Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Biotechnology Center, San Diego, CA 92121, USA.
  • 4. Chemical Biology & Therapeutics St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA(2).
  • 5. Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: [email protected].
PMID: 31786008 DOI: 10.1016/j.bmc.2019.115194
Abstract

Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer's Disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 Inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 Inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described.

Keywords
Alzheimer’s disease; BACE1 inhibitor; Conformational constraint; Cyclopropyl; Structure-based drug design.
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