Synthesis and selective coronary vasodilatory activity of 3,4-dihydro- 2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivatives: Novel potassium channel openers

Hidetsura Cho, Susumu Katoh, Shinsuke Sayama, Kengo Murakami, Hiroyuki Nakanishi, Yasuyuki Kajimoto, Hiroshi Ueno, Hisashi Kawasaki, Kazuo Aisaka, Itsuo Uchida

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Abstract

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-oxepyridazin-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-oxopyridazin-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, po) 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.

Original languageEnglish
Pages (from-to)3797-3805
Number of pages9
JournalJournal of Medicinal Chemistry
Volume39
Issue number19
DOIs
Publication statusPublished - 1996 Sep 13
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Cho, H., Katoh, S., Sayama, S., Murakami, K., Nakanishi, H., Kajimoto, Y., Ueno, H., Kawasaki, H., Aisaka, K., & Uchida, I. (1996). Synthesis and selective coronary vasodilatory activity of 3,4-dihydro- 2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivatives: Novel potassium channel openers. Journal of Medicinal Chemistry, 39(19), 3797-3805. https://doi.org/10.1021/jm960270l