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.
Elokdah
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Chemical Sciences, Wyeth-Ayerst Research, Princeton, NJ 08543, USA. elokdah@war.wyeth.com
Chai
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Ho
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Sulkowski
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D000284:Administration, Oral; D000818:Animals; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D009287:Naphthyridines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D008076:Cholesterol, HDL; D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; D007546:Isoquinolines; D009287:Naphthyridines