ABSTRACT
The synthesis and biological activity of novel glycoprotein IIb-IIla antagonists containing the 3,9-diazaspiro[5.5]undecane nucleus are described. The potent activity of these compounds as platelet aggregation inhibitors demonstrates the utility of the spirocyclic structures as a central template for nonpeptide RGD mimics.
Subject(s)
Platelet Aggregation Inhibitors/chemical synthesis , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Spiro Compounds/chemical synthesis , Administration, Oral , Animals , Aza Compounds/chemical synthesis , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Biological Availability , Blood Platelets/drug effects , Humans , Inhibitory Concentration 50 , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Rats , Rats, Sprague-Dawley , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis and biological activity of novel glycoprotein IIb-IlIa anatagonists containing 3-azaspiro[5.5]undec-9-yl nucleus are described. The potent activity of these compounds as platelet aggregation inhibitors demonstrates the utility of the monoazaspirocyclic structure as central template for nonpeptide RGD mimics.
Subject(s)
Platelet Aggregation Inhibitors/chemical synthesis , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Spiro Compounds/chemical synthesis , Administration, Oral , Animals , Aza Compounds/chemical synthesis , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Biological Availability , Blood Platelets/drug effects , Humans , Inhibitory Concentration 50 , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Vitronectin/antagonists & inhibitors , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
The substrate specificity at the active site of recombinant human synovial fluid phospholipase A2 (hs-PLA2) was investigated by the preparation of a series of short-chain phospholipid analogs and measurement of their enzymatic hydrolysis at concentrations well below the critical micelle concentration. Substrates used in the study included 1,2-dihexanoylglycerophospholipids, 1,2-bis(alkanoylthio)glycerophospholipids, and 1-O-alkyl-2-(alkanoylthio)phospholipids. Turnover was observed for only a few of the 1,2-dihexanoylglycerophospholipids, and the rate of hydrolysis was very low, near the limit of detection of the assay. In contrast, selected 2-(alkanoylthio)-glycerophospholipids were hydrolyzed by hs-PLA2 at much higher rates at concentrations well below their critical micelle concentration (cmc). Thus, the 1,2-bis(hexanoylthio)glycerophosphatidylmethanol exhibits a k(cat)/K(M) = 1800 L mol-1 s-1. Over the calculated log P (cLogP) range of 3-9, cLogP and log(k(cat)/K(M) were linearly related for compounds with straight-chain sn-1 and sn-2 substituents. At comparable cLogP's, the sn-1 ethers and thioesters were hydrolyzed at comparable rates. A negative charge in the phosphate head group was required for enzyme activity. Unsaturation, aromaticity, and branching in the sn-2 substituent reduce turnover dramatically. The same structural modifications in the sn-1 substituent have less effect on turnover. Certain of these substrates, e.g., 1,2-bis(hexanoylthio)glycerophosphatidylmethanol, may be useful in assaying for active site inhibitors of PLA2. The structure--activity relationships established here for substrates should serve as a reference for the structure--activity relationships of substrate-based inhibitors.
Subject(s)
Phospholipases A/antagonists & inhibitors , Phospholipids/metabolism , Synovial Fluid/enzymology , Binding Sites , Humans , Models, Molecular , Phospholipases A/metabolism , Phospholipases A2 , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Direct spectroscopic measurement of 1268 nm singlet oxygen emission from KO2 suspensions at room temperature in three non-protonic solvents--CCl4, Cl2FCCClF2, and C6F14 by the action of water is reported. The results clearly show that the singlet oxygen generation is due to a water induced reaction, and suggest that one role of the enzyme superoxide dismutase may be the protection of biological structures, for example, lipid membranes, from degradation by singlet oxygen.
Subject(s)
Oxygen/metabolism , Superoxides/metabolism , Water , Carbon Tetrachloride/pharmacology , Chemical Phenomena , Chemistry , Chlorofluorocarbons, Methane , Singlet Oxygen , Spectrophotometry, InfraredABSTRACT
Although certain gold [Au(I)] compounds have been used effectively in the treatment of rheumatoid arthritis for some years, the molecular basis for such therapeutic action has been unclear. One possible mechanism of the action of Au(I) compounds is that they protect unsaturated membrane lipids and proteins against oxidative degradation caused by activated phagocytes that are not properly regulated. In this study it has been shown that superoxide ion (O-2.), a product of activated phagocytes, can be oxidized to electronically excited singlet oxygen (O1(2)delta g), an agent that is capable of peroxidation of unsaturated fatty acid derivatives. It has also been shown that antiarthritic Au(I) compounds are effective deactivators of O1(2)delta g with quenching constants on the order of 10(7) M-1 sec-1.
Subject(s)
Auranofin , Oxygen , Arthritis, Rheumatoid/drug therapy , Chemical Phenomena , Chemistry, Physical , Humans , Kinetics , Lipid PeroxidesABSTRACT
Leukotrienes C4 and D4 (LTC4 and LTD4), possible mediators of cardiac dysfunction during inflammatory injury, may depress cardiac function by reducing coronary flow or by exerting a negative effect directly on the myocardium. We used an isovolumic rat heart preparation perfused at constant pressure and measured left ventricular developed pressure (mmHg), coronary flow (ml.min-1), oxygen extraction, and myocardial oxygen consumption and delivery (mumol O2.[gramme dry weight]-1.min-1) during infusion of five doses of angiotensin II, LTC4, LTD4 (approximately 10 to approximately 300 pmol.min-1), and noradrenaline (400 to 2000 pmol.min-1), or perfusion with medium which contained calcium at half-concentration. LTC4 and LTD4 were equipotent with angiotensin. At low effective doses, increased oxygen extraction offset the decrease in oxygen delivery, maintaining a stable level of oxygen consumption and left ventricular developed pressure. At the highest doses, angiotensin, LTC4 and LTD4 reduced coronary flow from 21 to 15, 21 to 13, and 21 to 13 ml.min-1, respectively. And, despite greater oxygen extraction of 59%, 58% and 65% for angiotensin, LTC4 and LTD4, left ventricular developed pressure fell from a baseline of 120 mmHg to 113, 106 and 92, respectively. In contrast, low calcium perfusion reduced left ventricular developed pressure (126 to 92) and oxygen extraction (46 to 30%) without changing coronary flow or oxygen delivery. These results suggest that LTC4 and LTD4 are potent coronary vasoconstricting agents which depress cardiac function by limiting oxygen delivery.
Subject(s)
Myocardial Contraction/drug effects , SRS-A/pharmacology , Angiotensin II/pharmacology , Animals , Calcium/pharmacology , Depression, Chemical , Dose-Response Relationship, Drug , Heart/physiology , Hemodynamics , In Vitro Techniques , Norepinephrine/pharmacology , Oxygen Consumption/drug effects , Perfusion , Rats , Rats, Inbred StrainsABSTRACT
10,10-Difluoro-13,14-dehydroprostacyclin was compared with natural prostacyclin (prostaglandin I2, PGI2) for vascular relaxing activity in vitro on helical strips of small canine mesenteric arteries (outside diameter < 1 mm) and bovine coronary arteries (outside diameter 1.5-2.5 mm) partially contracted with prostaglanding F2 alpha as well as in vivo in pentobarbital-anesthetized dogs. The difluoro analog was 3- to 4-fold more active than PGI2 in causing relaxation of both types of strips and appeared at least equipotent to PGI2 in its blood pressure lowering effect in dogs. When incubated with Krebs' bicarbonate solution (pH 7.4) at 37 degrees C, the biological half-life of the difluoro analog was about 24 hr compared to the 10- to 15-min half-life of PGI2 under similar conditions. However, when administered intravenously to dogs, the hemodynamic effects of the difluoro analog were of the same duration as those of PGI2.
