1. Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine β-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors.
- Author
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Wu YJ, Guernon J, Shi J, Marcin L, Higgins M, Rajamani R, Muckelbauer J, Lewis H, Chang C, Camac D, Toyn JH, Ahlijanian MK, Albright CF, Macor JE, and Thompson LA
- Subjects
- Amination, Amyloid Precursor Protein Secretases metabolism, Animals, Aspartic Acid Endopeptidases metabolism, Brain drug effects, Brain metabolism, Enzyme Inhibitors blood, Humans, Mice, Molecular Docking Simulation, Rats, Structure-Activity Relationship, Thiazines blood, Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid beta-Peptides metabolism, Aspartic Acid Endopeptidases antagonists & inhibitors, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Thiazines chemistry, Thiazines pharmacology
- Abstract
Truncation of the S3 substituent of the biaryl aminothiazine 2, a potent BACE1 inhibitor, led to a low molecular weight aminothiazine 5 with moderate activity. Despite its moderate activity, compound 5 demonstrated significant brain Aβ reduction in rodents. The metabolic instability of 5 was overcome by the replacement of the 6-dimethylisoxazole, a metabolic soft spot, with a pyrimidine ring. Thus, truncation of the S3 substituent represents a viable approach to the discovery of orally bioavailable, brain-penetrant BACE1 inhibitors.
- Published
- 2016
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