Discovery of amide and heteroaryl isosteres as carbamate replacements in a series of orally active γ-secretase inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 1; pp. 215 - 219
• Main Authors: McBriar, Mark D., Clader, John W., Chu, Inhou, Del Vecchio, Robert A., Favreau, Leonard, Greenlee, William J., Hyde, Lynn A., Nomeir, Amin A., Parker, Eric M., Pissarnitski, Dmitri A., Song, Lixin, Zhang, Lili, Zhao, Zhiqiang
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-01-2008; Elsevier
• Subjects: Alzheimer’s disease; Amides - chemistry; Amides - pharmacokinetics; Amides - pharmacology; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Biological and medical sciences; Carbamates - chemistry; Carbamates - pharmacokinetics; Carbamates - pharmacology; Cytochrome P-450 Enzyme Inhibitors; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacokinetics; Heterocyclic Compounds - pharmacology; Medical sciences; Mice; Neuropharmacology; Oxadiazoles - chemistry; Oxadiazoles - pharmacokinetics; Oxadiazoles - pharmacology; Pharmacology. Drug treatments; Piperidines - chemistry; Piperidines - pharmacokinetics; Piperidines - pharmacology; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacokinetics; Protease Inhibitors - pharmacology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Structure-Activity Relationship; γ-Secretase; Alzheimer’s disease; γ-Secretase; Cyclopropane derivatives; Rat; Alzheimer disease; Alcohol; Amides; Structure activity relation; Chlorine Organic compounds; Piperidine derivatives; Oxadiazole derivatives; Degenerative disease; Aspartic endopeptidases; Aromatic compound; Chemical synthesis; Alzheimer's disease; Nervous system diseases; Unspecific monooxygenase; Sulfonamide; Enzyme; Cytochrome P450; Rodentia; Oral administration; Enzyme inhibitor; Antialzheimer agent; Amyloid precursor protein; Cerebral disorder; Peptidases; In vivo; Vertebrata; Mammalia; Mouse; β Amyloid protein; Animal; Central nervous system disease; Hydrolases; Drug-metabolizing enzyme; Oxidoreductases; Pharmacokinetics
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2007.10.092

The design of amide and heteroaryl amide isosteres as replacements for the carbamate substructure in previously disclosed 2,6-disubstituted piperidine
N-arylsulfonamides is described. In several cases, amides lessened CYP liabilities in this class of γ-secretase inhibitors. Selected compounds showed significant reduction of Aβ levels upon oral dosing in a transgenic murine model of Alzheimer’s disease.