Georges Hirth

Substituted piperidines: Highly potent renin inhibitors due to induced fit adaptation of the active site

The identification, synthesis and activity of a novel class of piperidine renin inhibitors is presented. The most active compounds show activities in the picomolar range and are among the most potent renin inhibitors ever identified.

Piperidine-renin inhibitors compounds with improved physicochemical properties

Piperidine renin inhibitors with heterocyclic core modifications or hydrophilic attachments show improved physical properties (lower lipophilicity, improved solubility). Tetrahydroquinoline derivative rac-30 with a molecular weight of 517 and a log D(pH 7.4) of 1.9 displays potent and long lasting blood pressure lowering effects after oral administration to sodium depleted conscious marmosets.

In vitro characterisation of Ro 46-8443, the first non-peptide antagonist selective for the endothelin ETB receptor

We describe here Ro 46‐8443, the first non‐peptide endothelin ETB receptor selective antagonist. It displays up to 2000‐fold selectivity for ETB receptors both in terms of binding inhibitory potency and functional inhibition. The observed parallel rightward shift of concentration‐response curves with different antagonist concentrations is consistent with a competitive binding mode. Since Ro 46‐8443 selectively inhibits ETB receptor mediated responses, it is a valuable tool for clarifying the role of ETB receptors in pathology.

Discovery of Ro 48-5695: A potent mixed endothelin receptor antagonist optimized from bosentan

Abstract Implementation of a pyridylcarbamoyl group and an isopropylpyridylsulfonamide substituent as key components in the scaffold of Bosentan resulted in the identification of the potent orally active endothelin receptor antagonist Ro 48-5695. It shows affinities for ETA and ETB receptors in the low nanomolar range and high functional antagonistic potency in vitro.