| Synthesis and selective coronary vasodilatory activity of 3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivatives: novel potassium channel openers. | |
| | |
MedLine Citation:
|
PMID: 8809167 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
A variety of compounds having a benzopyran such as levcromakalim generally exhibit potent antihypertensive activity. During extensive investigations aimed toward identifying K+ channel openers having selective coronary vasodilation without potent hypotensive and tachycardiac effects, we synthesized a series of 3,4-dihydro-2H-1-benzopyran-3-ol derivatives modified at positions 2, 4, and 6 in the benzopyran ring. Initially, compounds having two methoxymethyl groups at position 2 were found to show a selective effect on coronary blood flow (CoBF) relative to mean arterial pressure (MAP) in anesthetized dogs. To find more potent vasodilators, various benzopyran derivatives modified at position 4 were synthesized and structure-activity relationships were examined by evaluation of the extent and duration of the increase in CoBF in anesthetized dogs. As a result, compounds having a (1,6-dihydro-6-oxopyridazin-3-yl)amino group at position 4, in addition to the two methoxymethyl groups at position 2, were found to be more potent and to have an improved duration of action. Among these compounds, JTV-506, (-)-(3S,4R)-6-cyano-3,4-dihydro-4-[(1,6-dihydro-1-methyl-6-oxopyridaz in-3-yl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol, exhibited good selectivity for its effect. Administration of this compound (0.03 mg/kg, p.o.) elicited an increase of CoBF without a change of systemic blood pressure and heart rate (HR) in conscious dogs. Further evaluation was performed with respect to (i) the selectivity of its action on the coronary artery versus the aorta and (ii) its effects on MAP, HR, and electrocardiographic ST elevation. As a result, JTV-506 was selected as a potent and selective coronary vasodilator with various pharmacological features favoring clinical development. |
| | |
Authors:
|
H Cho; S Katoh; S Sayama; K Murakami; H Nakanishi; Y Kajimoto; H Ueno; H Kawasaki; K Aisaka; I Uchida |
Related Documents
:
|
2829657 - Esmolol decreases the adverse effects of acute coronary artery occlusion on myocardial ... 7692177 - Acute hemodynamic and neurohumoral profile of dilevalol in hypertensive patients with i... 3489137 - The relationship between coronary pressure during reperfusion and myocardial recovery a... 2437287 - Inhibition of leukotriene d4-induced coronary vasoconstriction by leukotriene antagonis... 9631807 - Delivery of inhaled nitric oxide using the ohmeda inovent delivery system. 4447107 - A longitudinal study of blood pressure in childhood. |
Publication Detail:
|
Type: Journal Article |
Journal Detail:
|
Title: Journal of medicinal chemistry Volume: 39 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 1996 Sep |
Date Detail:
|
Created Date: 1996-11-04 Completed Date: 1996-11-04 Revised Date: 2003-11-14 |
Medline Journal Info:
|
Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: UNITED STATES |
Other Details:
|
Languages: eng Pagination: 3797-805 Citation Subset: IM |
Affiliation:
|
Japan Tobacco Inc., Central Pharmaceutical Research Institute, Osaka, Japan. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Benzopyrans / administration & dosage, chemical synthesis*, pharmacology Blood Pressure / drug effects Coronary Circulation / drug effects Coronary Vessels / drug effects*, physiology Dogs Female Heart Rate / drug effects Ion Channel Gating / drug effects* Male Models, Molecular Molecular Structure Potassium Channels / physiology* Pyridazines / administration & dosage, chemical synthesis*, pharmacology Rats Rats, Sprague-Dawley Structure-Activity Relationship Swine Vasodilator Agents / chemical synthesis*, pharmacology |
| Chemical | |
Reg. No./Substance:
|
0/6-cyano-3,4-dihydro-4-((1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)amino)-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol; 0/Benzopyrans; 0/Potassium Channels; 0/Pyridazines; 0/Vasodilator Agents |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Unsaturated side chain beta-11-hydroxyhexahydrocannabinol analogs.
Next Document: A novel series of (phenoxyalkyl)imidazoles as potent H3-receptor histamine antagonists.