title: Design and synthesis of dihydrobenzofuran amides as orally bioavailable, centrally active γ-secretase modulators.
abstract: We report the discovery and optimization of a novel series of dihydrobenzofuran amides as γ-secretase modulators (GSMs). Strategies for aligning in vitro potency with drug-like physicochemical properties and good microsomal stability while avoiding P-gp mediated efflux are discussed. Lead compounds such as 35 and 43 have moderate to good in vitro potency and excellent selectivity against Notch. Good oral bioavailability was achieved as well as robust brain Aβ42 lowering activity at 100 mg/kg po dose.
authors.affiliation: Neuroscience Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, USA. martin.pettersson@pfizer.com
authors.forename: Martin
authors.initials: M
authors.lastname: Pettersson
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Johnson
authors.forename: Chakrapani
authors.initials: C
authors.lastname: Subramanyam
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Bales
authors.forename: Christopher W
authors.initials: CW
authors.lastname: am Ende
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Fish
authors.forename: Michael E
authors.initials: ME
authors.lastname: Green
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Kauffman
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lira
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Mullins
authors.forename: Thayalan
authors.initials: T
authors.lastname: Navaratnam
authors.forename: Subas M
authors.initials: SM
authors.lastname: Sakya
authors.forename: Cory M
authors.initials: CM
authors.lastname: Stiff
authors.forename: Tuan P
authors.initials: TP
authors.lastname: Tran
authors.forename: Beth C
authors.initials: BC
authors.lastname: Vetelino
authors.forename: Longfei
authors.initials: L
authors.lastname: Xie
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Pustilnik
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Wood
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011485:Protein Binding; D051381:Rats
chemical_list: D000577:Amides; D001572:Benzofurans; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases