Discovery of a Novel, Potent Spirocyclic Series of γ-Secretase Inhibitors.
In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer's disease (AD), demonstrating reduction of amyloid-β (Aβ) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a(-) features improved selectivity for the inhibition of the PS-1 isoform of γ-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.
Department of Medicinal Chemistry, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Zhiqiang
Z
Zhao
Department of Medicinal Chemistry, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Dmitri A
DA
Pissarnitski
Department of Medicinal Chemistry, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Hubert B
HB
Josien
Department of Medicinal Chemistry, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Wen-Lian
WL
Wu
Department of Medicinal Chemistry, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Ruo
R
Xu
Department of Medicinal Chemistry, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Hongmei
H
Li
Department of Medicinal Chemistry, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
John W
JW
Clader
Department of Medicinal Chemistry, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Duane A
DA
Burnett
Department of Neurobiology, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Giuseppe
G
Terracina
Department of Neurobiology, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Lynn
L
Hyde
Department of Neurobiology, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Julie
J
Lee
Department of Neurobiology, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Lixin
L
Song
Department of Neurobiology, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Lili
L
Zhang
Department of Neurobiology, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Eric M
EM
Parker
D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C510791:MRK 560; D013449:Sulfonamides; D065729:Cytochrome P-450 CYP2C9; D053829:Amyloid Precursor Protein Secretases