Syntheses and pharmacological activities of novel optically active inhibitors of acyl-CoA: cholesterol O-acyltransferase: EAB-309 ((R)-N-2-(1,3-benzodioxol-4-yl)heptyl-N'-2,6-diisopropylphenylurea) and its enantiomer.

Novel and potent ACAT (acyl-CoA: cholesterol O-acyltransferase) inhibitors, (R)-N-2-(1,3-benzodioxol-4-yl)heptyl-N'-2,6-diisopropylphenylur ea (2a, EAB-309), and its enantiomer 2b (EAB-310), were prepared from 4-(1,3-benzodioxole)carbaldehyde (7) via optically active (R or S)-2-(1,3- benzodioxol-4-yl)heptanoic acid (12a or 12b). Compound 2a showed potent inhibitory effects on ACATs in vitro, and lowered plasma cholesterol in vivo. The IC50 value for inhibition of rat hepatic microsomal ACAT was 5 nM. The ED30 values of hypolipidemic activities in hamster and rat models were 0.25 and 0.75 mg/kg p.o., respectively. The results indicate that 2a has potential to be a novel hypocholesterolemic and antiatherosclerotic agent. The activities of 2a in vitro and in vivo were only several times more potent than those of the enantiomer 2b. Modeling studies suggested that the three-dimensional structures of the two enantiomers are similar to each other.

A novel class of cardiotonics. Synthesis and pharmacological properties of [4-(substituted-amino)phenyl]pyridazinones and related derivatives.

A series of [4-(substituted-amino)phenyl]pyridazinones and [4-(substituted-methyl)amino]phenyl]pyridazinones was synthesized and evaluated for inotropic activity in vitro and for cardiohemodynamic effects in vivo. Above all, 6-[4-(4-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (4, MCI-154) and 6-[4-(4-pyridylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone hydrochloride (5) showed extremely potent positive inotropic activity along with vasodilating activity. Regarding dP/dtmax (an indicator for cardiac contractility), ED30's (doses that increased dP/dtmax by 30%) of compounds 4 and 5 were 8.5 +/- 1.9 and 4.4 +/- 0.6 micrograms/kg, respectively, where that of amrinone was 471.9 +/- 94.1 micrograms/kg. Structure-activity relationships of these series are presented, and a plausible model of receptor binding is discussed.

Cardiovascular pharmacology of 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, a novel and potent cardiotonic agent with vasodilator properties.

The cardiovascular profile of 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (MCI-154), a novel cardiotonic agent structurally different from cardiac glycosides and beta-adrenoceptor agonists, was investigated in vivo. In anesthetized, open-chest dogs, MCI-154 (0.3-100 micrograms/kg i.v., bolus injection) produced dose-dependent increases in dP/dtmax and cardiac output, and decreases in arterial blood pressure and total peripheral resistance with a relatively small increase in heart rate. The positive inotropic effect of MCI-154 was more potent than those of amrinone and milrinone. In anesthetized, intact-chest dogs, infusion of MCI-154 (0.3-3 micrograms/kg/min i.v.) also exerted a positive inotropic effect. P.o. administrations of MCI-154 (10-300 micrograms/kg) increased dP/dtmax in conscious beagle dogs. The cardiotonic effect of MCI-154 was not attenuated by blockade of autonomic receptors, catecholamine depletion and prostaglandin synthesis inhibition. MCI-154 (0.3-30 micrograms i.a.) produced a direct vasodilator effect in the canine hind-limb. MCI-154 (3 and 30 micrograms/kg i.v.) was effective in heart failure models induced with high doses of propranolol or verapamil. The potent cardiotonic and vasodilator activities of MCI-154 revealed by the present study suggest that this agent would be an effective remedy for the treatment of heart failure.