ABSTRACT
[reaction: see text] Synthesis of the 8-amino-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ring system was accomplished by intramolecular cyclization of an iminium ion, derived from condensation of an amine and a substituted gamma-(1-imidazolyl)butyraldehyde. The reaction was used to produce conformationally restricted farnesyltransferase inhibitor analogues which exhibit improved in vivo metabolic stability.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Pyridines/chemical synthesis , Administration, Oral , Animals , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Indicators and Reagents , Models, Molecular , Molecular Conformation , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
Recently, it was found that large quantities of mannitol are present in unsporulated oocysts of the protozoan parasite Eimeria tenella and that these levels diminish during maturation (sporulation). Investigations into the metabolic role of mannitol have led to the discovery that a mannitol cycle is present in this parasite. Prior to these studies the mannitol cycle was found exclusively in fungi. The parasite cycle is similar to that in the fungi although there are distinct differences in coenzyme requirements. The enzymes involved in the parasite pathway include mannitol-1-phosphate dehydrogenase (EC 1.1.1.17), mannitol-1-phosphatase (EC 3.1.3.22), mannitol dehydrogenase (EC 1.1.1.67), and hexokinase (EC 2.7.1.1). Kinetic studies were conducted to determine the Km and specific activities of these enzymes at both ambient temperature (where sporulation occurs) and the chicken's body temperature (41 degrees C). The data suggest that mannitol is produced during oocyst formation in the chicken gut and accumulated as an energy reserve for sporulation. The apparent lack of mannitol kinase in the organism and the Km values for the dehydrogenases in the reverse direction all indicate that the cycle only proceeds in one direction. In addition to serving as an energy storage system the cycle may also function as an electron 'sink' for the parasite which must survive in the anaerobic environment of the gut.
