1H NMR (400 MHz, CDCl3), characteristic peaks: 7.65C7.78 (br m, 1H), 7.27C7.40 (m, 5H), 6.93C7.02 (br m, 1H), 6.80 (ddd, = 12.6, 8.5, 2.6 Hz, 1H), 4.06 (dd, = 11.7, 2.2 Hz, 1H), 3.53 (dd, = 10.2, 3.7 Hz, 1H), 2.50C2.61 (br m, Ginsenoside Rh1 1H), 1.62 (ddd, = 14, 4, 2.5 Hz, 1H), 0.89 (d, = 6.6 Hz, 3H). 539.2 [M C H]+. 523.2 [M + H]+. one of the underlying causes of Alzheimers disease (AD), which is the most common reason for cognitive decline in the elderly.1 AD pathology is characterized by the presence of extracellular plaques in the hippocampal and cortical regions of the brain, accompanied by intraneuronal neurofibrillary tangles and extensive neuronal loss.2 A, the major protein constituent of amyloid plaques, is derived from sequential cleavage of the type I integral membrane protein, amyloid precursor protein (APP), by two proteases: BACE1 and -secretase.3 Proteolytic cleavage of APP by BACE1, a member of the aspartyl protease family of enzymes, takes place within the endosome at Ginsenoside Rh1 low pH, generating a soluble N-terminal Mouse monoclonal to ER ectodomain of APP (sAPP) and C-terminal fragment (C99).4 Subsequent cleavage of the membrane-bound C99 fragment by -secretase liberates the various A peptide species, of which A40 and A42 Ginsenoside Rh1 are the predominant forms.5 Mutations in APP near the BACE1 cleavage site have been reported that either increase A generation and are associated with early onset AD or decrease A generation and protect against AD.6 Together, these data suggest that limiting the generation of A through inhibition of BACE1 is an attractive approach for the treatment of this disease. In recent years, the first generation of small molecule BACE1 inhibitors advanced into clinical studies. In contrast to the earlier chemical series, these compounds possess improved BACE1 potency and adequate CNS penetration and effectively lower A in the CSF of humans.7 While some clinical candidates continue to advance, unfortunately, there continues to be considerable attrition in this target space due to a range of safety findings, including hepatotoxicity and ocular toxicity. For example, BACE1 inhibitors from Eli Lilly (LY2811376) and Amgen (AMG-8718) led to accumulation of autofluorescent material and degeneration of the retinal pigment epithelium (RPE) layer of the eye in rat safety studies.8 In addition, Lilly terminated a phase II study with LY2886721 as a result of abnormal liver biochemical tests.9 With the requirement for longer duration studies in an aging population, a critical characteristic for a successful candidate will be fewer safety liabilities. As such, the next generations of BACE1 inhibitor clinical candidates will ideally exhibit improved CNS penetration, a reduced risk of safety findings, and a low daily dose. Results and Discussion Projected Human Dose We recently disclosed a novel series of thioamidine-containing BACE1 inhibitors, as represented by compound 1 (Figure ?(Figure1),1), possessing excellent overall properties including high CNS penetration (resulting from introduction of the methyl group). This was consistent with the notion that binding interactions for this series to CYP-P450s, rather than lipophilicity, were a key factor governing metabolic turnover. Open in a separate window Figure 7 Impact of a methyl group adjacent to sulfur (R2) on metabolism. To understand if this steric effect adjacent to the sulfur was a general solution to reducing clearance and CYP2D6 inhibition within Ginsenoside Rh1 this chemical series, we investigated the impact of adding the methyl group onto the set of heteroaryl-substituted THP analogues described above in Table 1. Compounds 9, 10, and 11 (R2 = Me) were prepared following the route described in Schemes 5C8, and the properties were compared directly to the matched molecular pairs in which R2 = H from Table 1. Analogous to compounds 7 and 8, the substituted oxazole 9 (R2.