ABSTRACT
Medicinal chemistry has been transformed by major technological and conceptual innovations over the last three decades: structural biology and bioinformatics, structure and property based molecular design, the concepts of multidimensional optimization (MDO), in silico and experimental high-throughput molecular property analysis. The novel technologies advanced gradually and in synergy with biology and Roche has been at the forefront. Applications in drug discovery programs towards new medicines in cardiovascular and metabolic diseases are highlighted to show impact and advancement: the early discovery of endothelin antagonists for endothelial dysfunction (Bosentan), 11-beta hydroxysteroid dehydrogenase (11ß-HSD1) inhibitors for dysregulated cellular glucocorticoid tonus (type 2 diabetes and metabolic syndrome) and non-covalent hormone sensitive lipase (HSL) inhibitors to study the scope of direct inhibition of lipolysis in the conceptual frame of lipotoxicity and type 2 diabetes.
Subject(s)
Cardiovascular Diseases/drug therapy , Chemistry, Pharmaceutical/trends , Drug Delivery Systems , Metabolic Diseases/drug therapy , Animals , Cardiovascular Agents/therapeutic use , Drug Design , HumansABSTRACT
Medicinal chemistry has been transformed by major technological and conceptual innovations over the last three decades: structural biology and bioinformatics, structure and property based molecular design, the concepts of multidimensional optimization (MDO), in silico and experimental high-throughput molecular property analysis. The novel technologies advanced gradually and in synergy with biology and Roche has been at the forefront. Applications in drug discovery programs towards new medicines in cardiovascular and metabolic diseases are highlighted to show impact and advancement: the early discovery of endothelin antagonists for endothelial dysfunction (Bosentan), 11-beta hydroxysteroid dehydrogenase (11ß-HSD1) inhibitors for dysregulated cellular glucocorticoid tonus (type 2 diabetes and metabolic syndrome) and non-covalent hormone sensitive lipase (HSL) inhibitors to study the scope of direct inhibition of lipolysis in the conceptual frame of lipotoxicity and type 2 diabetes.
ABSTRACT
A series of 25 compounds, some of which previously were described as inhibitors of human liver microsomal oxidosqualene cyclase (OSC), were tested as inhibitors of Saccharomyces cerevisiae, Trypanosoma cruzi, Pneumocystis carinii and Arabidopsis thaliana OSCs expressed in an OSC-defective strain of S. cerevisiae. The screening identified three derivatives particularly promising for the development of novel anti-Trypanosoma agents and eight derivatives for the development of novel anti-Pneumocystis agents.
Subject(s)
Antiparasitic Agents/chemical synthesis , Antiparasitic Agents/pharmacology , Arabidopsis/enzymology , Chemistry, Pharmaceutical/methods , Intramolecular Transferases/chemistry , Pneumocystis carinii/enzymology , Saccharomyces cerevisiae/enzymology , Trypanosoma cruzi/enzymology , Animals , Chromatography, Thin Layer , Drug Design , Humans , Intramolecular Transferases/metabolism , Microsomes, Liver/metabolism , Models, Chemical , Sterols/chemistryABSTRACT
We describe the structure-based design and synthesis of highly potent, orally bioavailable tissue factor/factor VIIa inhibitors which interfere with the coagulation cascade by selective inhibition of the extrinsic pathway.
Subject(s)
Anticoagulants/chemistry , Anticoagulants/pharmacology , Factor VIIa/antagonists & inhibitors , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Thromboplastin/antagonists & inhibitors , Administration, Oral , Animals , Anticoagulants/chemical synthesis , Biological Availability , Crystallography, X-Ray , Drug Design , Glycine/analogs & derivatives , Glycine/chemistry , Humans , Molecular Structure , Rats , Serine Proteinase Inhibitors/chemical synthesisABSTRACT
Proof of concept experiments have shown that tissue factor/factor VIIa inhibitors have antithrombotic activity without enhancing bleeding propensity. Starting from lead compounds generated by a biased combinatorial approach, phenylglycine amide tissue factor/factor VIIa inhibitors with low nanomolar affinity and good selectivity against other serine proteases of the coagulation cascade were designed, using the guidance of X-ray structural analysis and molecular modelling.
