title: Conformationally biased P3 amide replacements of beta-secretase inhibitors.
abstract: We have synthesized and evaluated a series of conformationally biased P3 amide replacements based on an isophthalamide lead structure. The studies resulted in the identification of the beta-secretase inhibitor 7m which has an in vitro IC(50)=35 nM. The synthesis and biological activities of these compounds are described.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. shawn_stachel@merck.com
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Stachel
authors.forename: Craig A
authors.initials: CA
authors.lastname: Coburn
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Steele
authors.forename: Min-Chi
authors.initials: MC
authors.lastname: Crouthamel
authors.forename: Beth L
authors.initials: BL
authors.lastname: Pietrak
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Munshi
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases; D015195:Drug Design; D010450:Endopeptidases / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010795:Phthalic Acids / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D010795:Phthalic Acids; D011480:Protease Inhibitors; C059768:isophthalate; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases