AZD3293 (Lanabecestat)

Description: Lanabecestat (formerly known as AZD3293 and LY3314814), is a novel potent, orally bioactive, highly permeable, brain-penetreable inhibitor of beta-secretase 1 cleaving enzyme (BACE) with a Ki of 0.4 nM. AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Abeta40, Abeta42, and sAbetaPPbeta. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Abeta40, Abeta42, and sAbetaPPbeta. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of Abeta. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.

References: J Alzheimers Dis. 2016; 50(4):1109-23.

Related CAS#:1383986-31-9 (HCl); 1628076-74-3