ABSTRACT
The antiglaucoma drugs dorzolamide (1) and brinzolamide (2) lower intraocular pressure (IOP) by inhibiting the carbonic anhydrase (CA) enzyme to reduce aqueous humor production. The introduction of a nitric oxide (NO) donor into the alkyl side chain of dorzolamide (1) and brinzolamide (2) has led to the discovery of NO-dorzolamide 3a and NO-brinzolamide 4a, which could lower IOP through two mechanisms: CA inhibition to decrease aqueous humor secretion (reduce inflow) and NO release to increase aqueous humor drainage (increase outflow). Compounds 3a and 4a have shown improved efficacy of lowering IOP in both rabbits and monkeys compared to brinzolamide (2).
Subject(s)
Carbonic Anhydrase Inhibitors/chemistry , Intraocular Pressure/drug effects , Nitric Oxide Donors/chemistry , Sulfonamides/chemistry , Thiazines/chemistry , Thiophenes/chemistry , Animals , Carbonic Anhydrase Inhibitors/pharmacokinetics , Carbonic Anhydrase Inhibitors/pharmacology , Drug Design , Glaucoma/drug therapy , Male , Nitric Oxide Donors/pharmacokinetics , Nitric Oxide Donors/pharmacology , Rabbits , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Thiazines/pharmacokinetics , Thiazines/pharmacology , Thiophenes/pharmacokinetics , Thiophenes/pharmacologyABSTRACT
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
A novel series of heterocycle-based analogs were prepared and evaluated for their in vitro and in vivo biological activity as human beta(3)-adrenergic receptor (AR) agonists. Several analogs demonstrated potent agonist activity at the beta(3)-AR, functional selectivity against beta(1)- and beta(2)-ARs, and favorable pharmacokinetic profiles in vivo. Compound 17 increased oxygen consumption in rats, a measure of energy expenditure, with an ED(20%) of 2mg/kg.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/therapeutic use , Obesity/drug therapy , Administration, Oral , Adrenergic beta-Agonists/administration & dosage , Adrenergic beta-Agonists/pharmacokinetics , Adrenergic beta-Agonists/pharmacology , Animals , Biological Availability , RatsABSTRACT
The convergent, highly enantioselective synthesis of rhizoxin D, a natural product possessing potent antitumor and antifungal bioactivity, is described. The C(1)-C(9) fragment of the molecule was synthesized utilizing a threefold pseudosymmetric intermediate ultimately derived from gamma-butyrolactone. The central core of rhizoxin D was prepared via a chiral resolution/asymmetric aldol protocol. Several methods for the generation of the polyene fragment were explored, and the side-chain was ultimately prepared from serine in six steps. The unification of the left and right wings of the molecule was achieved using a one-step olefination protocol, and the macrocyclization was carried out using a Horner-Emmons olefination at the C(2)-C(3) olefin.
