title: Application of the bicyclo[1.1.1]pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent and orally active γ-secretase inhibitor.
abstract: Replacement of the central, para-substituted fluorophenyl ring in the γ-secretase inhibitor 1 (BMS-708,163) with the bicyclo[1.1.1]pentane motif led to the discovery of compound 3, an equipotent enzyme inhibitor with significant improvements in passive permeability and aqueous solubility. The modified biopharmaceutical properties of 3 translated into excellent oral absorption characteristics (~4-fold ↑ C(max) and AUC values relative to 1) in a mouse model of γ-secretase inhibition. In addition, SAR studies into other fluorophenyl replacements indicate the intrinsic advantages of the bicyclo[1.1.1]pentane moiety over conventional phenyl ring replacements with respect to achieving an optimal balance of properties (e.g., γ-secretase inhibition, aqueous solubility/permeability, in vitro metabolic stability). Overall, this work enhances the scope of the [1.1.1]-bicycle beyond that of a mere "spacer" unit and presents a compelling case for its broader application as a phenyl group replacement in scenarios where the aromatic ring count impacts physicochemical parameters and overall drug-likeness.
authors.affiliation: Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, USA. Antonia.Stepan@pfizer.com
authors.forename: Antonia F
authors.initials: AF
authors.lastname: Stepan
authors.forename: Chakrapani
authors.initials: C
authors.lastname: Subramanyam
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Efremov
authors.forename: Jason K
authors.initials: JK
authors.lastname: Dutra
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: O'Sullivan
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: DiRico
authors.forename: W Scott
authors.initials: WS
authors.lastname: McDonald
authors.forename: Annie
authors.initials: A
authors.lastname: Won
authors.forename: Peter H
authors.initials: PH
authors.lastname: Dorff
authors.forename: Charles E
authors.initials: CE
authors.lastname: Nolan
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Becker
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Pustilnik
authors.forename: David R
authors.initials: DR
authors.lastname: Riddell
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Kauffman
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Kormos
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.forename: Yasong
authors.initials: Y
authors.lastname: Lu
authors.forename: Steven H
authors.initials: SH
authors.lastname: Capetta
authors.forename: Michael E
authors.initials: ME
authors.lastname: Green
authors.forename: Kapil
authors.initials: K
authors.lastname: Karki
authors.forename: Evelyn
authors.initials: E
authors.lastname: Sibley
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Atchison
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hallgren
authors.forename: Christine E
authors.initials: CE
authors.lastname: Oborski
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Robshaw
authors.forename: Blossom
authors.initials: B
authors.lastname: Sneed
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
mesh_terms: D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D005260:Female; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010420:Pentanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: C574649:2-(N-((3-(1,2,4-oxadiazol-3-yl)bicyclo(1.1.1)pentan-1-yl)methyl)-4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide; D001643:Bridged Bicyclo Compounds; D010069:Oxadiazoles; D010420:Pentanes; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases