title: Structure-based design, synthesis, and memapsin 2 (BACE) inhibitory activity of carbocyclic and heterocyclic peptidomimetics.
abstract: Molecular modeling based on the X-ray crystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM99-2) of BACE led to the design and synthesis of a series of constrained P(1)' analogues. A cyclopentane ring was incorporated in 1 spanning the P(1)' Ala methyl group and the adjacent methylene carbon atom of the chain. Progressive truncation at the P(2)'-P(4)' sites led to a potent truncated analogue 5 with good selectivity over Cathepsin D. Using the same backbone replacement concept, a series of cyclopentane, cyclopentanone, tetrahydrofuran, pyrrolidine, and pyrrolidinone analogues were synthesized with considerable variation at the P and P' sites. The cyclopentanone and 2-pyrrolidinone analogues 45 and 57 showed low nM BACE inhibition. X-ray cocrystal structures of two analogues 5 and 45 revealed excellent convergence with the original inhibitor 1 structure while providing new insights into other interactions which could be exploited for future modifications.
authors.affiliation: Department of Chemistry, Université de Montréal, C. P. 6128, Succursale Centre-Ville, Montréal, Province Quebec, Canada H3C 3J7. stephen.hanessian@umontreal.ca
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanessian
authors.forename: Hongying
authors.initials: H
authors.lastname: Yun
authors.forename: Yihua
authors.initials: Y
authors.lastname: Hou
authors.forename: Gaoqiang
authors.initials: G
authors.lastname: Yang
authors.forename: Malken
authors.initials: M
authors.lastname: Bayrakdarian
authors.forename: Eric
authors.initials: E
authors.lastname: Therrien
authors.forename: Nicolas
authors.initials: N
authors.lastname: Moitessier
authors.forename: Silvio
authors.initials: S
authors.lastname: Roggo
authors.forename: Siem
authors.initials: S
authors.lastname: Veenstra
authors.forename: Marina
authors.initials: M
authors.lastname: Tintelnot-Blomley
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rondeau
authors.forename: Christian
authors.initials: C
authors.lastname: Ostermeier
authors.forename: André
authors.initials: A
authors.lastname: Strauss
authors.forename: Paul
authors.initials: P
authors.lastname: Ramage
authors.forename: Paolo
authors.initials: P
authors.lastname: Paganetti
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
authors.forename: Claudia
authors.initials: C
authors.lastname: Betschart
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry; D010450:Endopeptidases; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D003517:Cyclopentanes; D005663:Furans; D010455:Peptides; D011759:Pyrrolidines; D011760:Pyrrolidinones; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D002402:Cathepsin D