ABSTRACT
A series of purine derivatives was prepared and examined for selective inotropic activity in vitro and in vivo. Thioether-linked derivatives were superior to their oxygen and nitrogen isosteres. Substitution of electron-withdrawing groups on the benzhydryl moiety of these agents increased potency. The best compound of the study, 17 (carsatrin), was examined further and demonstrated selective oral activity as a positive inotrope. These compounds are presumed to act by affecting the kinetics of the cardiac sodium channel by analogy to the prototypic agent DPI 201106 (1). Their high selectivity for increasing contractile force and dP/dt without affecting blood pressure or heart rate is consistent with this mechanism. Carsatrin (17) was selected as a potential development candidate.
Subject(s)
Cardiotonic Agents/chemical synthesis , Cardiotonic Agents/pharmacology , Mercaptopurine/analogs & derivatives , Myocardial Contraction/drug effects , Piperazines/chemical synthesis , Purines/chemical synthesis , Purines/pharmacology , Animals , Blood Pressure/drug effects , Dogs , Ferrets , Heart Rate/drug effects , Male , Mercaptopurine/chemical synthesis , Mercaptopurine/pharmacology , Molecular Structure , Papillary Muscles/drug effects , Papillary Muscles/physiology , Piperazines/pharmacology , Sodium Channels/drug effects , Sodium Channels/physiology , Stimulation, Chemical , Structure-Activity RelationshipABSTRACT
A series of heterocyclic (aryloxy)alkylamines of structures II and III were prepared and found to possess gastric antisecretory activity. Of the variety of substituted thiazoles, benzoxazoles, and benzothiazoles prepared, thiazole 18, benzoxazole 32, and benzothiazole 47 exhibited gastric antisecretory potency comparable to that of ranitidine in vivo in the pylorous ligated rat model. In an isolated rabbit parietal system, the series of thiazoles, benzoxazoles, and benzothiazoles also demonstrated similar potency to that of ranitidine toward the inhibition of both histamine-stimulated and dcAMP-stimulated uptake of amino[14C]pyrine. These compounds inhibited the H+K+-sensitive ATPase enzyme in isolated gastric microsomes. A direct correlation existed between inhibition of 14C uptake, in vivo antisecretory activity, and inhibition of the H+K+-ATPase enzyme. The more potent antisecretory compounds 18, 32, and 47 were also the more potent enzyme inhibitors. These data suggest that the mechanism responsible for the observed in vitro and in vivo gastric antisecretory activity, in these series of compounds, is a consequence of the inhibition of the H+K+-sensitive ATPase enzyme.
Subject(s)
Adenosine Triphosphatases/antagonists & inhibitors , Amines/chemical synthesis , Gastric Acid/metabolism , Amines/pharmacology , Aminopyrine/metabolism , Animals , Benzothiazoles , Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacology , Bucladesine/pharmacology , Chemical Phenomena , Chemistry , Cimetidine/pharmacology , Gastric Mucosa/drug effects , H(+)-K(+)-Exchanging ATPase , Histamine/pharmacology , Ligation , Male , Omeprazole/pharmacology , Parietal Cells, Gastric/drug effects , Parietal Cells, Gastric/metabolism , Pyloric Antrum/physiology , Ranitidine/pharmacology , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacologyABSTRACT
The synthesis of a variety of pyrrolo[1,2-c]quinazolines and pyrrolo[1,2-c]quinazolinones is described. Several of these compounds have exhibited antihypertensive properties in the spontaneously hypertensive rat (SHR). Structure-activity comparisons have indicated that optimal activity is obtained in both the 2-carbethoxydihydroquinazoline series (C) and 2-carbethoxyquinazolinone series (D) when there is either a carbethoxy or cyanoethyl group at position 6 and no substitution in the benzene ring, while optimal activity is obtained in the 2-methyl-quinazolinone series (D) when both position 6 and the benzene ring are unsubstituted.
