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

Autor:	Wenyuan Qian, Michael J. Frohn, Michael D. Bartberger, Stephen J. Wood, Albert Amegadzie, Aaron C. Siegmund, Ning Chen, Jennifer R. Allen, Dean Hickman, Helming Tan, Paul H. Wen, Longbin Liu, Matthew P. Bourbeau, Douglas A. Whittington
Rok vydání:	2020
Předmět:	Hydrocarbons Fluorinated Clinical Biochemistry Molecular Conformation Pharmaceutical Science Alkenes 01 natural sciences Biochemistry Structure-Activity Relationship chemistry.chemical_compound Drug Development Amide Drug Discovery Aspartic Acid Endopeptidases Humans Structure–activity relationship Enzyme Inhibitors Molecular Biology ADME Olefin fiber Dose-Response Relationship Drug 010405 organic chemistry Organic Chemistry Stereoisomerism Amides Combinatorial chemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry HEK293 Cells chemistry Molecular Medicine Bioisostere Amyloid Precursor Protein Secretases
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 30:127240
ISSN:	0960-894X
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::395d3ff250cc89083eaa72586d38d376 https://doi.org/10.1016/j.bmcl.2020.127240 Zobrazit plný text záznamu Full Text from ScienceDirect