Henri Ramuz

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.

Simultaneous determination of chloroquine and selected calcium(II) channel blockers by high-performance liquid chromatography.

Abstract Chloroquine (CQ), which is the primary drug for treatment and prophylaxis against malaria, has become ineffective because of the high prevalence of CQ-resistant P. falciparum parasites, but resistant parasites exposed to a Ca(II) channel blocker become as susceptible to CQ as sensitive parasites. A reversed-phase liquid chromatographic method is described for simultaneously determining CQ, its metabolites desethyl-CQ and bisdesethyl-CQ, the Ca(II) channel blocker verapamil, and the tiapamil analogue N-(3,4-dimethoxyphenethyl)- N-methyl-2-(naphthyl)-m-dithiane-2-propylamine hydrochloride. The analytes were separated by gradient elution with acetonitrile and 1-heptane sulfonic acid; the detector wavelength was 232 nm. The mean recovery from spiked plasma was 100.1 ± 2.28 (SD). Within-day retention times were reproducible to within ± 0.03 SD of mean values and the lower limit of detection was about 2 ng of each analyte.

Ro 11-2933, a potential drug in the treatment of cancer and malaria: synthesis and physicochemical properties; potential metabolites

Abstract Ro 11–2933, 4b , a compound with minor cardiovascular activity has been shown to reverse multidrug resistance in cancer cells as well as chloroquine resistance in Plasmodium falciparum . A useful synthesis of the drug is described. Alkylation of dithiane (2) with chloroalkylamine (3) affords 4b as a crystalline compound in a very good yield. The synthesis of its potential metabolites 7 and 11 has also been carried out.