2. Academic Validation
  3. Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints

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

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: mergottdu@lilly.com.
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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