Diastereoselective Synthesis of 2‑Phenyl-3-(trifluoromethyl)piperazines as Building Blocks for Drug Discovery

The synthesis of enantiomerically pure <i>cis</i>- and <i>trans</i>-2-phenyl-3-(trifluoromethyl)­piperazines is described. It involved, as the key step, a diastereoselective nucleophilic addition of the Ruppert–Prakash reagent (TMSCF₃) to α-amino sulfinylimines bearing Ellman’s auxiliary. This methodology allows an entry into hitherto unknown trifluoromethylated and stereochemically defined piperazines, key scaffold components in medicinal chemistry

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

1,4-Oxazine β‑Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads

1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine p<i>K</i>_a while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer’s disease

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