ABSTRACT
The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension.
Subject(s)
Antihypertensive Agents/pharmacology , Drug Discovery , Hypertension/drug therapy , Soluble Guanylyl Cyclase/metabolism , Antihypertensive Agents/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
A modular, selective approach to complex α-tertiary substituted malononitriles is reported. The method takes advantage of ß-ester-substituted α,α-dinitrile alkenes as highly reactive, chemoselective electrophiles for 1,4-additions with organometallic nucleophiles to produce functionally and sterically dense all-carbon quaternary centers. In the presence of a chiral ester auxiliary bearing an aromatic ring, the 1,4-addition occurs with good to excellent selectivity due to favorable cation-π interactions. The highly functionalized malononitriles represent versatile building blocks and can be applied toward efficient, highly selective syntheses of 5,5-disubstituted pyrrolopyrimidinones.
ABSTRACT
Simple tin derivatives, Cp*2SnCl2 (1) and Ph2SnCl2 (2), catalyze the hydrophosphination of alkene substrates with diphenylphosphine. Competitive dehydrocoupling to give Ph4P2 was observed, but this side reaction can be mitigated when the catalysis is conducted under an H2 atmosphere. Efforts to prepare stable tin bis(phosphido) compounds commonly resulted in decomposition to Ph4P2. Lewis acidic inorganic tin compounds do not show dehydrocoupling reactivity. It was found that the Lewis acid, B(C6F5)3, is able to engage in the hydrophosphination of alkenes, but it is poorly effective under the conditions tested.
ABSTRACT
Two cobalt compounds, Cp*Co(CO)I2 (1) and CpCo(CO)I2 (2) (Cp* = η(5)-C5Me5, Cp = η(5)-C5H5), catalyze the dehydrogenation of ammonia borane under either anaerobic or aerobic conditions and are also effective hydrogenation catalysts for alkenes and alkynes using ammonia borane as a hydrogen source, also in the presence of air.
ABSTRACT
Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be potent p38 MAP kinase inhibitors. These compounds significantly suppress TNF-alpha release in both cellular and LPS-stimulated whole blood assays. They also displayed excellent PK profiles across three animal species. Quinolinone at 10 mpk showed comparable oral efficacy to that of dexamethasone at 1 mpk in a murine collagen-induced arthritis model.
Subject(s)
Enzyme Inhibitors/pharmacology , Naphthyridines/chemistry , Piperidines/chemistry , Quinolones/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Arthritis, Experimental , Collagen/chemistry , Dexamethasone/chemistry , Dogs , Haplorhini , Humans , Inhibitory Concentration 50 , Lipopolysaccharides/metabolism , Mice , Models, Chemical , Rats , Time Factors , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/chemistry , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Development for a class of potent 3,4-dihydropyrido(3,2-d)pyrimidone inhibitors of p38a MAP kinase is described. Modification of N-1 aryl and C-6 arylsulfide in 3,4-dihydropyrido(3,2-d)pyrimidone analogues for the interaction with the hydrophobic pockets in p38 active site is also discussed.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Pyrimidinones/chemical synthesis , Enzyme Inhibitors/pharmacology , Kinetics , Molecular Structure , Pyrimidinones/pharmacology , Structure-Activity Relationship , p38 Mitogen-Activated Protein KinasesABSTRACT
A new class of p38 antagonists based on 3,4-dihydropyrido[3,2,-d]pyrimidine scaffold has been developed. These inhibitors exhibit unprecedented selectivity towards p38 over other very closely related kinases. Compounds 25, 33, and 34 were identified as benchmark analogues for follow-up studies. They show good potency for enzyme inhibition and excellent functional activity.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Drug Design , Indicators and Reagents , Structure-Activity Relationship , p38 Mitogen-Activated Protein KinasesABSTRACT
The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38alpha MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38alpha inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 piperidinyl substituents led to the identification of 15i which gave excellent suppression of TNF-alpha production in LPS-stimulated whole blood (IC(50)=10nM) and good oral exposure in rats (F=68%, AUCn PO=0.58 microM h).
