Scott Martin Sheehan

The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central Aβ Pharmacodynamic Responses in Mice, Dogs, and Humans

BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimers disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Similar potent and persistent amyloid β lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.

A four component coupling strategy for the synthesis of d-phenylglycinamide-derived non-covalent factor Xa inhibitors

A novel isonitrile derivative was synthesized and used in an Ugi four component coupling reaction to explore aryl group substitution effects on inhibition of the coagulation cascade serine protease factor Xa.

Proof-of-concept pharmacodynamic assessment of a prototypic BACE1 inhibitor at steady-state using IV infusion dosing in the PDAPP transgenic mouse model of Alzheimer's disease

Background: BACE1 is a key protease involved in Abeta generation but has proven challenging as a drug target. Many early BACE1 inhibitors which were optimized for potency at the enzyme, failed to achieve sufficient brain penetration to demonstrate central pharmacodynamic (PD) effects in vivo. Methods: Young PDAPP transgenic mice (n 1⁄4 10/group) were surgically implanted with a central catheter and dosed IV over a period of 22 hrs with vehicle or BACE1 inhibitor at 4.3, 8.6 or 14.4 mg/ml at 60 ul/hr rate. Doses were determined by prior pharmacokinetic measurements using a single IV bolus and calculated to reach steady-state levels exceeding their cellular IC50. Plasma and brain Ab (1-X) levels were measured using human-specific total Ab (1-X) ELISAs. The proximal biomarkers of BACE1 cleavage, C99 and sAPPbeta, were also measured in brain homogenates using appropriately configured sandwich ELISAs. Compound exposure was measured in plasma and remaining brain using LC/MS. Results: Steady-state IV infusion of this small molecule BACE1 inhibitor in PDAPP transgenic mice resulted in dose-dependent decreases in Ab, C99 and sAPPbeta measured in brain. Plasma Ab levels were not measurable beyond the lowest dose due to the robust effect of treatment. The reductions in brain biomarkers were dose-dependent and a change of similar magnitude occurred in all three in both brain regions (w71-85% decrease in the high dose group). The exposures measured in the plasma and brains increased with dose and were consistent with the dose-dependent efficacy observed. There were no adverse reactions to these doses in this study. Conclusions: IV administration of a prototypic BACE1 small molecule inhibitor to steady state produces robust reduction of brain Abeta levels by a mechanism of action consistent with BACE1 inhibition in vivo. Robust BACE1 inhibition can be maintained for 22 hours without significant adverse events offering hope for targeting this protease for the treatment of AD.