ABSTRACT
Various 1,2-isothiazolidine-1,1-dioxide (gamma-sultam) derivatives containing an antioxidant moiety, 2,6-di-tert-butylphenol substituent, were prepared. Some compounds, which have a lower alkyl group at the 2-position of the gamma-sultam skeleton, showed potent inhibitory effects on both cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO), as well as production of interleukin (IL)-1 in in vitro assays. They also proved to be effective in several animal arthritic models without any ulcerogenic activities. Among these compounds, (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1, 2-isothiazolidine-1,1-dioxide (S-2474) was selected as an antiarthritic drug candidate and is now under clinical trials. The structure-activity relationships (SAR) examined and some pharmacological evaluations are described.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Arthritis/drug therapy , Cyclic S-Oxides/chemical synthesis , Isoenzymes/pharmacology , Lipoxygenase Inhibitors , Prostaglandin-Endoperoxide Synthases/pharmacology , Thiazoles/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis, Experimental/drug therapy , Blood Platelets/drug effects , Blood Platelets/metabolism , Cyclic S-Oxides/adverse effects , Cyclic S-Oxides/therapeutic use , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/therapeutic use , Dinoprostone/antagonists & inhibitors , Dinoprostone/biosynthesis , Edema/chemically induced , Edema/drug therapy , Female , Gastric Mucosa/drug effects , Humans , Interleukin-1/antagonists & inhibitors , Interleukin-1/pharmacology , Leukotriene B4/antagonists & inhibitors , Leukotriene B4/biosynthesis , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/therapeutic use , Male , Membrane Proteins , Rats , Rats, Inbred Lew , Structure-Activity Relationship , Synovial Membrane/drug effects , Synovial Membrane/metabolism , Thiazoles/adverse effects , Thiazoles/therapeutic useSubject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Bridged Bicyclo Compounds/pharmacology , Norbornanes/pharmacology , Prostaglandin D2/metabolism , Receptors, Immunologic , Receptors, Prostaglandin/administration & dosage , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Blood Platelets/drug effects , Bridged Bicyclo Compounds/administration & dosage , Bridged Bicyclo Compounds/chemistry , Guinea Pigs , Humans , Norbornanes/administration & dosage , Norbornanes/chemistry , Receptors, Prostaglandin/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
New platelet activating factor (PAF) antagonists, 3 were synthesized by replacing the charged phosphate and trimethylammonium moieties with sulfonamide and heterocyclic quaternary ammonium functionalities, respectively (PAF-sulfonamide isosteres). Darmstoff phosphatidic acid analogues of this class (Darmstoff-sulfonamide isosteres), 6 were also synthesized. The activity of these compounds as PAF antagonists was evaluated from their in vitro inhibitory effect on PAF-induced platelet aggregation in rabbit platelet-rich plasma. Among the compounds tested, some of the 2-methoxypropane derivatives with an octadecylcarbamoyloxy or octadecylcarbamoylthio side chain at the 1-position and a propylsulfonamide function bearing a terminal polar substituent such as a quaternary quinolinium or substituted quinolinium group at the 3-position were found to be the most potent (IC50 = 0.3-0.6 microM).
Subject(s)
Platelet Activating Factor/antagonists & inhibitors , Platelet Aggregation Inhibitors/chemical synthesis , Sulfonamides/chemical synthesis , Animals , In Vitro Techniques , Isomerism , Male , Platelet Activating Factor/chemistry , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacology , Rabbits , Structure-Activity Relationship , Sulfonamides/pharmacologyABSTRACT
In a continuing effort to obtain more potent platelet activating factor (PAF) antagonists, we tried to synthesize a series of PAF-sulfonamide isosteres in which the substituent at the 2-position was modified to an acetoxy equivalent other than the methoxy group. These modifications produced highly active PAF antagonists. Compound 3-[2-(5-methyl-2H-tetrazol-2-yl)-3-(octadecylcarbamoyloxy) propylaminosulfonyl]propylquinolinium iodide (52) showed the most potent activity in the in vitro inhibitory effect on PAF-induced platelet aggregation in rabbit platelet-rich plasma (IC50 = 125 nM) and also in the in vivo protective effect on PAF-induced lethality in mice, with prolonged duration of action. Optically active enantiomers of this compound were synthesized and the (S)-(-)-isomer (IC50 = 87 nM) was found to be three times more potent that the (R)-(+)-isomer (IC50 = 289 nM), clearly exemplifying the enantioselectivity in the PAF-antagonist action of this novel compound.
Subject(s)
Glycerol/chemistry , Platelet Activating Factor/antagonists & inhibitors , Sulfonamides/chemical synthesis , Animals , In Vitro Techniques , Male , Mice , Mice, Inbred Strains , Platelet Activating Factor/chemistry , Platelet Activating Factor/toxicity , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacology , Rabbits , Structure-Activity Relationship , Sulfonamides/pharmacologyABSTRACT
Thromboxane A2 receptor antagonists 11a, 15a, 26a, 30a, 34a, 36a, 46a, 52a, 61a, 72a, and 82a, which contain 6-oxabicyclo[3.1.0]hexane, 6-thiabicyclo[3.1.0]hexane, bicyclo[3.1.0]hexane, or 6,6-dimethylbicyclo[3.1.0]hexane ring systems with heptenoic and (phenylsulfonyl)amino side chains, and their corresponding sodium salts and methyl esters were synthesized. This study then examined the inhibitory effects of their sodium salts for the platelet aggregation induced by arachidonic acid with rabbit platelet-rich plasma and platelet aggregation induced by collagen with rat washed platelets.