Discovery and hit-to-lead optimization of novel allosteric glucokinase activators.

We report on a hit generation and hit-to-lead program of a novel class of glucokinase activators (GKAs). Hit compounds, activators at low glucose concentration only were identified by vHTS. Scaffold modification reliably afforded activators also at high substrate level. Potency was increased by introduction of a hydrogen bond acceptor as proposed by molecular docking. Replacement of the initial alkylene linkers with a rigid 1,2-phenylene motif followed by further studies eventually furnished a series of potent lead compounds exhibiting steep SAR.

A vHTS approach for the identification of beta-adrenoceptor ligands.

Using a vHTS based on a pharmacophore alignment on known beta3-adrenoceptor ligands, a set of intriguing beta-adrenoceptor ligands was identified, optimization of which resulted in a selective and potent human beta2-AR antagonist.

Thienopyrimidines as ß3-adrenoceptor agonists: hit-to-lead optimization.

Resulting from a vHTS based on a pharmacophore alignment on known ß3-adrenoceptor ligands, an aryloxypropanolamine scaffold comprising a thienopyrimidine moiety was further optimized as a human ß3-AR agonist, yielding a lead compound with an excellent cellular activity of EC(50)=20 pM, selectivity over hß1- and hß2-adrenoceptors and a promising safety profile.

N-substituted 2'-(aminoaryl)benzothiazoles as kinase inhibitors: hit identification and scaffold hopping.

Starting with a hit from vHTS attained by a docking procedure of virtual compounds into ATP pockets of different kinases applying the 4SCan technology, variations of the adenine mimic resulted in the identification of promising scaffolds, giving rise to in vitro IC(50) values in the nanomolar range on different kinases down to 63nM.

Substituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization.

Based on an (aminoaryl)benzothiazole quinazoline hit structure for kinase inhibition, a systematic optimization program resulted in a lead structure allowing for inhibitory activities in cellular phosphorylation assays in the low nanomolar range.