title: Discovery of (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): metabolically stable γ-secretase Inhibitors that selectively inhibit the production of amyloid-β over Notch.
abstract: Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aβ in the CSF of healthy human volunteers.
authors.affiliation: Department of Medicinal Chemistry, Elan Pharmaceuticals , 180 Oyster Point Boulevard, South San Francisco, California 94080, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Probst
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Aubele
authors.forename: Simeon
authors.initials: S
authors.lastname: Bowers
authors.forename: Darren
authors.initials: D
authors.lastname: Dressen
authors.forename: Albert W
authors.initials: AW
authors.lastname: Garofalo
authors.forename: Roy K
authors.initials: RK
authors.lastname: Hom
authors.forename: Andrei W
authors.initials: AW
authors.lastname: Konradi
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Marugg
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Mattson
authors.forename: Martin L
authors.initials: ML
authors.lastname: Neitzel
authors.forename: Chris M
authors.initials: CM
authors.lastname: Semko
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Jenifer
authors.initials: J
authors.lastname: Smith
authors.forename: Minghua
authors.initials: M
authors.lastname: Sun
authors.forename: Anh P
authors.initials: AP
authors.lastname: Truong
authors.forename: Xiaocong M
authors.initials: XM
authors.lastname: Ye
authors.forename: Ying-Zi
authors.initials: YZ
authors.lastname: Xu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Dappen
authors.forename: Jacek J
authors.initials: JJ
authors.lastname: Jagodzinski
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Keim
authors.forename: Brian
authors.initials: B
authors.lastname: Peterson
authors.forename: Lee H
authors.initials: LH
authors.lastname: Latimer
authors.forename: David
authors.initials: D
authors.lastname: Quincy
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Erich
authors.initials: E
authors.lastname: Goldbach
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Ness
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Quinn
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Sauer
authors.forename: Karina
authors.initials: K
authors.lastname: Wong
authors.forename: Hongbin
authors.initials: H
authors.lastname: Zhang
authors.forename: Wes
authors.initials: W
authors.lastname: Zmolek
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Brigham
authors.forename: Dora
authors.initials: D
authors.lastname: Kholodenko
authors.forename: Kang
authors.initials: K
authors.lastname: Hu
authors.forename: Grace T
authors.initials: GT
authors.lastname: Kwong
authors.forename: Michael
authors.initials: M
authors.lastname: Lee
authors.forename: Anna
authors.initials: A
authors.lastname: Liao
authors.forename: Ruth N
authors.initials: RN
authors.lastname: Motter
authors.forename: Patricia
authors.initials: P
authors.lastname: Sacayon
authors.forename: Pamela
authors.initials: P
authors.lastname: Santiago
authors.forename: Christopher
authors.initials: C
authors.lastname: Willits
authors.forename: Frédérique
authors.initials: F
authors.lastname: Bard
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bova
authors.forename: Susanna S
authors.initials: SS
authors.lastname: Hemphill
authors.forename: Lam
authors.initials: L
authors.lastname: Nguyen
authors.forename: Lany
authors.initials: L
authors.lastname: Ruslim
authors.forename: Kevin
authors.initials: K
authors.lastname: Tanaka
authors.forename: Pearl
authors.initials: P
authors.lastname: Tanaka
authors.forename: William
authors.initials: W
authors.lastname: Wallace
authors.forename: Ted A
authors.initials: TA
authors.lastname: Yednock
authors.forename: Guriqbal S
authors.initials: GS
authors.lastname: Basi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000134:cerebrospinal fluid / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D000072056:Transcription Factor HES-1
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D051792:Basic Helix-Loop-Helix Proteins; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D018398:Homeodomain Proteins; D011720:Pyrazoles; D011804:Quinolines; D012333:RNA, Messenger; D051880:Receptors, Notch; D013449:Sulfonamides; D000072056:Transcription Factor HES-1; C586851:4-cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo(4,3-c)quinoline; C489734:Hes1 protein, mouse; C573127:(R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo(4,3-c)quinoline