ABSTRACT
A series of para-substituted phenoxypropanolamines has been synthesized and tested for beta-adrenoceptor blocking activity. Some derivatives (8, 11, 12, 20, 21) exhibited greater in vitro potency than the reference drugs metoprolol and propranolol. This series, in contrast to propranolol but similar to metoprolol, possesses cardioselectivity. The 3-[p-[(cycloalkylmethoxy)ethyl]phenoxy]-1-substituted-amino-2-prop anol derivatives 8 (cyclopropylmethoxyethyl: betaxolol) and 11 (cyclobutylmethoxyethyl) produced antihypertensive effects in spontaneously hypertensive rats. Betaxolol (Kerlon, 8) was found to exhibit an appropriate preclinical pharmacological and human pharmacokinetic profile (elevated oral bioavailability and prolonged plasma half-life) for the treatment of chronic cardiovascular diseases such as hypertension and angina.
Subject(s)
Adrenergic beta-Antagonists/chemical synthesis , Cardiovascular Diseases/drug therapy , Propanolamines/chemical synthesis , Adrenergic beta-Antagonists/metabolism , Adrenergic beta-Antagonists/pharmacology , Anesthetics, Local/pharmacology , Animals , Antihypertensive Agents/pharmacology , Betaxolol , Biotransformation , Chronic Disease , Female , Guinea Pigs , In Vitro Techniques , Kinetics , Male , Propanolamines/metabolism , Propanolamines/pharmacology , Rana esculenta , Rats , Structure-Activity RelationshipABSTRACT
A series of N2-[(acylamino)alkyl]-6,7-dimethoxy-2,4-quinazolinediamines was synthesized as potential alpha 1-adrenoceptor antagonists. When administered to spontaneously hypertensive rats at 10 mg/kg po, a number of propanediamine derivatives showed good antihypertensive activity, whereas the ethanediamine derivatives, albeit being structurally more closely related to prazosin, were devoid of this property. The most active derivative, N-[3-[(4-amino-6, 7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarbo xamide hydrochloride, alfuzosin (12), showed high selectivity for peripheral alpha 1-postjunctional adrenoceptors. At equiactive antihypertensive doses, its effect on the pressor response to postural changes in conscious dog was less marked than that shown by prazosin. In the light of these results, alfuzosin was selected for clinical evaluation.
Subject(s)
Hypertension/drug therapy , Quinazolines/therapeutic use , Animals , Chemical Phenomena , Chemistry , Male , Quinazolines/chemical synthesis , Rats , Rats, Inbred SHR , Structure-Activity RelationshipABSTRACT
A series of (4-substituted phenyl-1-piperazinyl)alkyl 2-aminobenzoates and 2-aminonicotinates has been prepared and screened for analgesic and antiinflammatory properties in mice and rats. The tabulated results reveal several 2-(4-substituted phenyl-1-piperazinyl)ethyl 2-(7- or 8-substituted 4-quinolinylamino)benzoates to be six to nine times more potent analgesics than the reference compounds (glafenine and aminopyrine) and to possess minor antinflammatory activity. Compound 45, 2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl 2-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoate (antrafenine), showed marked analgesic activity, long duration of action, and excellent tolerance in pharmacological and toxicological studies, as well as in clinical trials.