Optimization of 1,4-Oxazine β‑Secretase 1 (BACE1) Inhibitors Toward a Clinical Candidate

In previous studies, the introduction of electron withdrawing groups to 1,4-oxazine BACE1 inhibitors reduced the p<i>K</i>_a of the amidine group, resulting in compound <b>2</b> that showed excellent in vivo efficacy, lowering Aβ levels in brain and CSF. However, a suboptimal cardiovascular safety margin, based on QTc prolongation, prevented further progression. Further optimization resulted in the replacement of the 2-fluoro substituent by a CF₃-group, which reduced hERG inhibition. This has led to compound <b>3</b>, with an improved cardiovascular safety margin and sufficiently safe in GLP toxicity studies to progress into clinical trials

Identification of a Novel Orally Bioavailable Phosphodiesterase 10A (PDE10A) Inhibitor with Efficacy in Animal Models of Schizophrenia.

We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo­[1,2-<i>a</i>]­pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound <b>25a</b> for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure–activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead <b>25a</b> are described