2. Academic Validation
  3. The development of a structurally distinct series of BACE1 inhibitors via the (Z)-fluoro-olefin amide bioisosteric replacement

The development of a structurally distinct series of BACE1 inhibitors via the (Z)-fluoro-olefin amide bioisosteric replacement

  • Bioorg Med Chem Lett. 2020 Jul 15;30(14):127240. doi: 10.1016/j.bmcl.2020.127240.
Michael Frohn 1,  Longbin Liu 2,  Aaron C Siegmund 2,  Wenyuan Qian 2,  Albert Amegadzie 2,  Ning Chen 2,  Helming Tan 3,  Dean Hickman 4,  Stephen Wood 5,  Paul H Wen 5,  Michael D Bartberger 6,  Douglas A Whittington 6,  Jennifer R Allen 2,  Matthew P Bourbeau 2
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States. Electronic address: mfrohn@amgen.com.
  • 2 Medicinal Chemistry, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States.
  • 3 Pre-Pivotal Drug Product, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States.
  • 4 Pharmicokinetics and Drug Metabolism, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States.
  • 5 Neuroscience Research, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States.
  • 6 Molecular Engineering, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States.
PMID: 32527542 DOI: 10.1016/j.bmcl.2020.127240
Abstract

The (Z)-fluoro-olefin amide bioisosteric replacement is an effective tool for addressing various shortcomings of the parent amide. In an effort to fine tune ADME properties of BACE1 preclinical candidate AM-6494, a series of structurally distinct (Z)-fluoro-olefin containing analogs was developed that culminated in compound 15. Herein, we detail design considerations, synthetic challenges, structure activity relationship (SAR) studies, and in vivo properties of an advanced compound in this novel series of BACE1 inhibitors.

Keywords

(Z)-fluoro-olefin; BACE1; Bioisostere.

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