ABSTRACT
A series of chemically stable TXA2/PGH2 analogues modeled after the structure of the natural products was prepared in search of useful inhibitors of TXA2/PGH2-mediated pathophysiology. Each of the 16 isomers implied in structure 1 was prepared in chiral form and evaluated for activity in vitro in platelets and smooth muscle. Depending on relative side chain and carbinol stereochemistry, TXA2/PGH2 agonist and antagonist and, surprisingly, PGD2/PGI2 agonist activities were observed. The enantiomers possessing the alpha heterocycle shown in 1 were generally more potent than their mirror-image isomers.
Subject(s)
Bridged Bicyclo Compounds/pharmacology , Bridged-Ring Compounds/pharmacology , Fatty Acids, Monounsaturated , Prostaglandin Endoperoxides, Synthetic , Prostaglandin Endoperoxides , Prostaglandins H , Thromboxane A2/analogs & derivatives , Animals , Bridged Bicyclo Compounds/chemical synthesis , Chemical Phenomena , Chemistry , Fatty Acids, Unsaturated , Guinea Pigs , Humans , Isomerism , Molecular Conformation , Muscle Contraction/drug effects , Muscle, Smooth/physiology , Platelet Aggregation/drug effects , Prostaglandin Endoperoxides/antagonists & inhibitors , Prostaglandin Endoperoxides, Synthetic/antagonists & inhibitors , Prostaglandin H2 , Prostaglandins H/antagonists & inhibitors , Rats , Structure-Activity Relationship , Thromboxane A2/antagonists & inhibitors , Thromboxane-A Synthase/antagonists & inhibitors , X-Ray DiffractionSubject(s)
Epoprostenol/metabolism , Prostaglandins/metabolism , Receptors, Cell Surface/metabolism , Receptors, Prostaglandin/metabolism , Thromboxane A2/pharmacology , Thromboxanes/pharmacology , Adenylyl Cyclases/metabolism , Animals , Guinea Pigs , Muscle Contraction/drug effects , Platelet Aggregation/drug effects , Receptors, Epoprostenol , Receptors, Prostaglandin/drug effects , Receptors, Thromboxane , Structure-Activity Relationship , Thromboxane A2/analogs & derivatives , Thromboxane A2/chemical synthesis , Thromboxane A2/metabolism , Thromboxane-A Synthase/antagonists & inhibitors , Trachea/drug effectsABSTRACT
A series of mercaptoacyl amino acids and related compounds was synthesized and evaluated for inhibition of angiotensin-converting enzyme (ACE) in order to determine the nature and importance of the putative interaction between ACE and the amide moiety of inhibitors such as captopril (3-mercapto-2-methylpropanoyl-L-proline). It was concluded that the interaction involves a hydrogen bond from a donor site on ACE to the oxygen of the amide carbonyl. Compounds in which the amide moiety is replaced by other groups (ester, ketone, sulfonamide) capable of accepting a hydrogen bond are effective inhibitors, but compounds in which only the geometrical features of the amide are retained are ineffective inhibitors. The presence of an NH group is not necessary for effective inhibition. The activity of a series of mercaptoacyl cycloalkyl carboxylic acids parallels the activity of the isosteric series of mercaptoacyl imino acids.
Subject(s)
Amino Acids, Sulfur/chemical synthesis , Angiotensin-Converting Enzyme Inhibitors , Amino Acids, Sulfur/pharmacology , Animals , Chemical Phenomena , Chemistry, Physical , Hydrogen Bonding , In Vitro Techniques , Lung/enzymology , Molecular Conformation , Rabbits , Structure-Activity RelationshipABSTRACT
A newly synthesized 9 alpha-homo-9,11-epoxy-5,13-prostadienoic acid analogue, SQ 26, 536, (8(R)9(S)11(R)12(S)-9 alpha-homo-9,11-epoxy-5(Z), 13(E)-15S-hydroxyprostadienoic acid) inhibited arachidonic acid (AA)-induced platelet aggregation with an I50 value of 1.7 microM. SQ 26,536 did not inhibit prostaglandin (PG) synthetase activity of bovine seminal vesicle microsomes or thromboxane (Tx) synthetase activity of lysed human blood platelets. SQ 26,536 also inhibited platelet aggregation induced by epinephrine (secondary phase), 9,11-azoPGH2 and collagen but did not inhibit the primary phase of epinephrine-induced aggregation or ADP-induced platelet aggregation. SQ 26,538 (8(R)9(S)11(R)12(S)-9 alpha-homo-9,11-epoxy-5(Z),13(E)-15R-hydroxyprostadienoic acid), a 15-epimer of SQ 26,536, induced platelet aggregation with an A50 value of 2.5 microM. SQ 26,536 competitively inhibited SQ 26,538-induced platelet aggregation with a Ki value of 3 microM. Neither indomethacin, a PG synthetase inhibitor, nor SQ 80,338 (1-(3-phenyl-2-propenyl)-1H-imidazole), a Tx synthetase inhibitor, inhibited SQ 26,538- or 9,11-azoPGH2-induced platelet aggregation. These data indicate that SQ 26,536 and SQ 26,538 are stable antagonist and agonist, respectively, of the human blood platelet thromboxane receptor.
