title: Discovery and optimization of a novel spiropyrrolidine inhibitor of β-secretase (BACE1) through fragment-based drug design.
abstract: The aspartyl protease β-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of Aβ-peptide, a major component of plaques in the brains of Alzheimer's disease (AD) patients, and inhibition of this enzyme has emerged as a major strategy for pharmacologic intervention in AD. An X-ray-based fragment screen of Pfizer's proprietary fragment collection has resulted in the identification of a novel BACE binder featuring spiropyrrolidine framework. Although exhibiting only weak inhibitory activity against the BACE enzyme, the small compound was verified by biophysical and NMR-based methods as a bona fide BACE inhibitor. Subsequent optimization of the lead compound, relying heavily on structure-based drug design and computational prediction of physiochemical properties, resulted in a nearly 1000-fold improvement in potency while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability.
authors.affiliation: Pfizer Worldwide Research, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United States. ivan.efremov@pfizer.com
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Efremov
authors.forename: Felix F
authors.initials: FF
authors.lastname: Vajdos
authors.forename: Kris A
authors.initials: KA
authors.lastname: Borzilleri
authors.forename: Steven
authors.initials: S
authors.lastname: Capetta
authors.forename: Hou
authors.initials: H
authors.lastname: Chen
authors.forename: Peter H
authors.initials: PH
authors.lastname: Dorff
authors.forename: Jason K
authors.initials: JK
authors.lastname: Dutra
authors.forename: Steven W
authors.initials: SW
authors.lastname: Goldstein
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Mansour
authors.forename: Alexander
authors.initials: A
authors.lastname: McColl
authors.forename: Stephen
authors.initials: S
authors.lastname: Noell
authors.forename: Christine E
authors.initials: CE
authors.lastname: Oborski
authors.forename: Thomas N
authors.initials: TN
authors.lastname: O'Connell
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: O'Sullivan
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Binqing
authors.initials: B
authors.lastname: Wei
authors.forename: Jane M
authors.initials: JM
authors.lastname: Withka
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D011759:Pyrrolidines; D013141:Spiro Compounds; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human