beta-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer’s disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived then inhibitors such as 1 with low nanomolar potency against beta-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce A beta(40) levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.
An exploration of the SAR of the side chain of a novel tricyclic series of gamma-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PSI selective inhibitor of gamma-secretase (A beta 40 IC50 = 1.

3 nM). Compound (-)-16 demonstrated excellent lowering of A beta after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer’s disease.
Inhibition of BACE1 to prevent brain A beta peptide formation is a potential disease modifying approach to the treatment of Alzheimer’s disease. Despite over a decade of drug discovery efforts, the identification of brain penetrant BACE1 inhibitors that substantially lower CNS A beta levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold.

Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF A beta 40 levels when administered orally to Drug_discovery rats.
Targeting neuroinflammation may be a new strategy to combat Alzheimer’s disease. An aminopyridazine 1b previously reported as a novel antineuroinflammatory agent was considered to have a potential therapeutic effect for Alzheimer’s disease. In this study, we further explored the chemical space to identify more potent antineuroinflammatory agents and validate their in vivo efficacy in an animal model. Compound 14 was finally identified as an effective agent with comparable in vivo efficacy to the marketed drug donepezil in counteracting spatial learning and working memory impairment in an A beta-induced Alzheimer’s mouse model.

The discovery of a new series of gamma-secretase modulators is disclosed www.selleckchem.com/products/Gefitinib.html Starting from a triterpene glycoside gamma-secretase modulator that gave a very low brain-to-plasma ratio, initial SAR and optimization involved replacement of a pendant sugar with a series of morpholines. This modification led to two compounds with significantly improved central nervous system (CNS) exposure.
Tri- and tetracyclic nitrogen-bridgehead compounds were designed and synthesized to yield micromolar cholinesterase (chE), inhibitors.