Benzazaborinines as Novel Bioisosteric Replacements of Naphthalene: Propranolol as an Example

Two benzazaborinine analogues of propranolol were synthesized and extensively profiled <i>in vitro</i> and <i>in vivo</i>. These analogues showed potency and physicochemical and <i>in vitro</i> ADME–tox profiles comparable to propranolol. In addition, both benzazaborinine analogues showed excellent bioavailability and brain penetration following subcutaneous administration in a pharmacokinetic study in rats. These studies unveil the potential of aromatic azaborinines as bioisosteric replacements of naphthalene in drug discovery programs

Pyrido[4,3‑<i>e</i>][1,2,4]triazolo[4,3‑<i>a</i>]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors

A novel series of pyrido­[4,3-<i>e</i>]­[1,2,4]­triazolo­[4,3-<i>a</i>]­pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and <i>in vivo</i> receptor occupancy data are given for two representative compounds <b>6</b> and <b>12</b>

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

Discovery of <i>N</i>‑(Pyridin-4-yl)-1,5-naphthyridin-2-amines as Potential Tau Pathology PET Tracers for Alzheimer’s Disease

A mini-HTS on 4000 compounds selected using 2D fragment-based similarity and 3D pharmacophoric and shape similarity to known selective tau aggregate binders identified <i>N</i>-(6-methylpyridin-2-yl)­quinolin-2-amine <b>10</b> as a novel potent binder to human AD aggregated tau with modest selectivity versus aggregated β-amyloid (Aβ). Initial medicinal chemistry efforts identified key elements for potency and selectivity, as well as suitable positions for radiofluorination, leading to a first generation of fluoroalkyl-substituted quinoline tau binding ligands with suboptimal physicochemical properties. Further optimization toward a more optimal pharmacokinetic profile led to the discovery of 1,5-naphthyridine <b>75</b>, a potent and selective tau aggregate binder with potential as a tau PET tracer