ABSTRACT
Novel bi-functional compounds with a nitric oxide (NO)-releasing moiety bound to a dorzolamide scaffold were investigated. Several compounds were synthesized and their activity as selective carbonic anhydrase inhibitors (CAI) evaluated in vitro on recombinant hCA type I, II and IV enzyme isoforms where they showed different degrees of potency and selectivity to hCA II. A high resolution X-ray crystal structure for the CA II adduct with 8 confirmed the high affinity of this class of compounds for the enzyme. Compounds 4, 6, and 8 showed highly potent and efficacious NO-mediated properties as assessed by their vascular relaxant effect on methoxamine-precontracted rabbit aortic rings. Finally, compounds 4 and 6 exerted potent intraocular pressure (IOP) lowering effects in vivo in normotensive rabbits thereby anticipating their potential for the treatment of hypertensive glaucoma.
Subject(s)
Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase Inhibitors/therapeutic use , Glaucoma, Open-Angle/drug therapy , Nitric Oxide/chemistry , Sulfonamides/therapeutic use , Thiophenes/therapeutic use , Animals , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Crystallography, X-Ray , Drug Discovery , Models, Molecular , Molecular Structure , Rabbits , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Thiophenes/chemical synthesis , Thiophenes/chemistryABSTRACT
The development of a series of novel 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. Optimization of microsomal clearance led to the identification of 9c, whose kinase selectivity is reported.
Subject(s)
JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Mitogen-Activated Protein Kinase 8/antagonists & inhibitors , Mitogen-Activated Protein Kinase 8/metabolism , Structure-Activity RelationshipABSTRACT
Gonadotropin releasing hormone (GnRH) plays an important role in the biology of reproduction. The use of GnRH receptor antagonists has been reported in the literature for the treatment of breast, ovarian, and prostate cancers. In this article, we report the synthesis, in vitro characterization, pharmacokinetics, and pharmacodynamics of an orally bioavailable, potent, small molecule GnRH receptor antagonist N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5-[3,3,6-trimthyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide (compound 1).
Subject(s)
Indenes/chemical synthesis , Morpholines/chemical synthesis , Pyrimidines/chemical synthesis , Receptors, LHRH/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Humans , In Vitro Techniques , Indenes/chemistry , Indenes/pharmacology , Inositol Phosphates/biosynthesis , Male , Morpholines/chemistry , Morpholines/pharmacology , Orchiectomy , Pituitary Gland/metabolism , Pyrimidines/chemistry , Pyrimidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Recombinant Proteins/metabolism , Structure-Activity Relationship , Testis/drug effects , Testis/metabolism , Testosterone/antagonists & inhibitors , Testosterone/metabolismABSTRACT
A new one-pot nitration employing tetramethylammonium nitrate and trifluoromethanesulfonic anhydride in dichloromethane to provide a ready source of the nitronium triflate nitrating agent is presented. Rapid and selective nitration with a variety of aromatic and heteroaromatic substrates is achieved resulting in the synthesis of several novel organic compounds. A distinct advantage is the removal of undesired byproducts by aqueous workup. This very mild nitration permits large-scale syntheses and gives high isolated product yields that often require no further purification. This tetramethylammonium nitrate-based nitration also has been applied to microwave-assisted conditions, and the results with several compounds are outlined.
