H. Cho et al., SYNTHESIS AND SELECTIVE COROLLARY VASODILATORY ACTIVITY OF IHYDRO-2,2-BIS(METHOXYMETHYL)-2H-1-BENZOPYRAN-3-OL DERIVATIVES - NOVEL POTASSIUMCHANNEL OPENERS, Journal of medicinal chemistry, 39(19), 1996, pp. 3797-3805
A variety of compounds having a benzopyran such as levcromakalim gener
ally exhibit potent antihypertensive activity. During extensive invest
igations aimed toward identifying K+ channel openers having selective
coronary vasodilation without potent hypotensive and tachycardiac effe
cts, we synthesized a series of 3,4-dihydro-2H-1-benzopyran-3-ol deriv
atives modified at positions 2, 4, and 6 in the benzopyran ring. Initi
ally, compounds having two methoxymethyl groups at position 2 were fou
nd to show a selective effect on coronary blood flow (CoBF) relative t
o mean arterial pressure (MAP) in anesthetized dogs. To find more pote
nt vasodilators, various benzopyran derivatives modified at position 4
were synthesized and structure-activity relationships were examined b
y evaluation of the extent and duration of the increase in CoBF in ane
sthetized dogs. As a result, compounds having a (1,6-dihydro-6-oxopyri
dazin-3-yl)amino group at position 4, in addition to the two methoxyme
thyl groups at position 2, were found to be more potent and to have an
improved duration of action. Among these compounds, JTV-506, mino]-2,
2-bis(methoxymethyl)-2H-1-benzopyran-3-ol, exhibited good selectivity
for its effect. Administration of this compound (0.03 mg/kg, po) elici
ted an increase of CoBF without a change of systemic blood pressure an
d heart rate (HR) in conscious dogs. Further evaluation was performed
with respect to (i) the selectivity of its action on the coronary arte
ry versus the aorta and (ii) its effects on MAP, HR, and electrocardio
graphic ST elevation. As a result, JTV-506 was selected as a potent an
d selective coronary vasodilator with various pharmacological features
favoring clinical development.