Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of 4-phenyl-1,4-dihydropyridines substituted at the ortho and meta positions of the phenyl ring with NO-donating furoxan moieties and their non-NO-releasing furazan analogues were synthesized and pharmacologically characterized. The vasodilator activities of these compounds were evaluated on rat aorta and expressed as EC50 values or as EC50iGC values when obtained in the presence of inhibitors of guanylate cyclase methylene blue (MB) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Affinities to 1, 4-DHP receptors on Ca2+ channels, expressed as IC50 values, were determined through displacement experiments of [3H]nitrendipine on rat cortex homogenates. A linear correlation between IC50 and EC50 values was found for compounds unable to release NO. EC50calcd values for derivatives containing NO-donor moieties, expression of the Ca2+-blocking component of their vasodilator activity, were interpolated on this linear regression. They showed a good correspondence with EC50iGC values determined in the presence of soluble guanylate cyclase inhibitors. Analysis of EC50iGC/EC50 ratios provided a useful tool to distinguish well-balanced hybrids from derivatives biased toward Ca2+-blocking or NO-dependent vasodilator activity. A detrimental effect on affinity to the 1, 4-DHP receptor, due to substitution at the ortho and meta positions of the 4-phenyl ring, was observed. SAR to explain this effect is proposed.
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PMID:New 1,4-dihydropyridines conjugated to furoxanyl moieties, endowed with both nitric oxide-like and calcium channel antagonist vasodilator activities. 987 9

Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impairments of the NO-sGC signaling pathway have been implicated in the pathogenesis of cardiovascular and other diseases. Direct stimulation of sGC represents a promising therapeutic strategy particularly for the treatment of pulmonary hypertension (PH), a disabling disease associated with a poor prognosis. Previous sGC stimulators such as the pyrazolopyridines BAY 41-2272 and BAY 41-8543 demonstrated beneficial effects in experimental models of PH, but were associated with unfavorable drug metabolism and pharmacokinetic (DMPK) properties. Herein we disclose an extended SAR exploration of this compound class to address these issues. Our efforts led to the identification of the potent sGC stimulator riociguat, which exhibits an improved DMPK profile and exerts strong effects on pulmonary hemodynamics and exercise capacity in patients with PH. Riociguat is currently being investigated in phase III clinical trials for the oral treatment of PH.
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PMID:Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. 1926 60

Novel guanylate cyclase stimulators are disclosed. Design, synthesis, SAR, and pharmacological profile of the compounds are discussed.
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PMID:Identification of acidic heterocycle-substituted 1H-pyrazolo[3,4-b]pyridines as soluble guanylate cyclase stimulators. 2338 9