Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibitors of phosphodiesterases 3 and 4, the main cyclic AMP (cAMP) degrading enzymes in arteries, may have therapeutic potential in cerebrovascular disorders. We analysed the effects of such phosphodiesterases in guinea pig cerebral arteries with organ bath technique and cyclic nucleotide assays. Guinea pig and human cerebral arteries were used for phosphodiesterase assays. Cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone), a phosphodiesterase 3 inhibitor, was compared to conventional phosphodiesterase 3 and 4 inhibitors. Phosphodiesterases 3 and 4 were the major contributors to total cAMP hydrolysis in the arteries examined. The phosphodiesterase 3 inhibitors additionally attenuated cyclic GMP (cGMP) hydrolysis, but relaxant responses were not dependent on an intact endothelium or on the nitric oxide-cGMP pathway. Conversely, the phosphodiesterase 4 inhibitor used was endothelium-dependent and affected by cGMP levels. This suggests that phosphodiesterase 3 inhibitors are still effective under conditions with possible dysfunctional nitric oxide-cGMP pathway, such as in ischemic stroke or cerebral vasospasm.
 ...
PMID:Analysis of the effects of phosphodiesterase type 3 and 4 inhibitors in cerebral arteries. 1506 60

During the course of the past two decades, our group has worked towards the development of increasingly potent inotropic agents by making structural modifications to compounds derived from 3,4-dihydro-2(1H)-quinolinone (DHQO) and related analogues. Herein, we describe the design and synthesis of a new series of DHQO derivatives and the subsequent evaluation of their positive inotropic activity towards left atrium stroke volume in isolated rabbit-heart preparations. Some of these derivatives presented favorable in vitro activities compared with the reference drug, milrinone, and compound 10a, in particular is currently being investigated as a preclinical drug candidate. This review also describes our progress towards the development of DHQO derivatives and related analogues with positive inotropic activities from 1999 to 2013.
...
PMID:The progress towards the development of DHQO derivatives and related analogues with inotropic effects. 2403 11