title: Monosubstituted γ-lactam and conformationally constrained 1,3-diaminopropan-2-ol transition-state isostere inhibitors of β-secretase (BACE).
abstract: The synthesis, evaluation, and structure-activity relationships of a class of γ-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of γ-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented.
authors.affiliation: Department of Neuroscience Discovery Chemistry, Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA. boyk@bms.com
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Boy
authors.forename: Jason M
authors.initials: JM
authors.lastname: Guernon
authors.forename: Jianliang
authors.initials: J
authors.lastname: Shi
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Toyn
authors.forename: Jere E
authors.initials: JE
authors.lastname: Meredith
authors.forename: Donna M
authors.initials: DM
authors.lastname: Barten
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Burton
authors.forename: Charles F
authors.initials: CF
authors.lastname: Albright
authors.forename: Jovita
authors.initials: J
authors.lastname: Marcinkeviciene
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Good
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tebben
authors.forename: Jodi K
authors.initials: JK
authors.lastname: Muckelbauer
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Camac
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Lentz
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.forename: Richard E
authors.initials: RE
authors.lastname: Olson
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.forename: Lorin A
authors.initials: LA
authors.lastname: Thompson
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007769:Lactams; D053829:Amyloid Precursor Protein Secretases