Hassan M. Elokdah

Design and synthesis of tricyclic derivatives as high density lipoprotein cholesterol enhancers

A pharmacophore for increasing HDLC was proposed based on common structural features of non-thio-containing compounds with HDLC enhancing properties. A search of the compound database identified various series of these non-thio-containing compounds, including a novel tricyclic imidazoisoquinolone. Preparation of 1-aryl-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamides using a novel and widely applicable one-step process from 2-acyl benzoic acids is reported. Reaction of diamines with 1-aryl-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamides and related aza-analogues proceeded with regio-control to furnish imidazoisoquinolones, pyrimidoisoquinolones, and imidazonaphthyridines. NMR studies and X-ray crystallography confirmed the regiochemistry of the products. Compounds of these series increased concentrations of HDLC in test animals following oral administration.

Effects of 2-(substituted-sulfanyl)-3,5-dihydro-imidazole-4-one and 2-(substituted-sulfanyl)-1H-imidazole-4,5-dione derivatives on serum HDL-cholesterol

A series of 2-substituted sulfanyl-3,5-dihydro-imidazole-4-ones and 2-substituted sulfanyl-1H-imidazole-4,5-diones was prepared and shown to increase high density lipoprotein cholesterol over other lipid fractions. Compound 1f showed efficacy in additional animal models. The major metabolite of 1f was isolated and its synthesis is reported. The effects of the metabolite on the lipid profile in rats were investigated.

Novel human metabolites of the angiotensin-II antagonist tasosartan and their pharmacological effects.

Three novel metabolites of the angiotensin-II (A-II) receptor antagonist tasosartan have been identified in humans, and the syntheses and pharmacologic profiling of these metabolites are reported. Each metabolite bound the human A-II receptor with IC(50)s between 20 and 45nM. The in vivo effects of these compounds in attenuating the pressor response to angiotensin-II challenge in anesthetized rats were also investigated. An unsaturated diol metabolite exhibited in vivo efficacy at intravenous doses of 1 and 3mg/kg, while the other metabolites, both carboxylic acids, had no significant effect at the same doses.