Suraj Shivappa Shetty

Isoindolines: a new series of potent and selective endothelin-A receptor antagonists.

1,3-Disubstituted isoindolines have been discovered as a new class of potent functional ET(A) selective receptor antagonists through pharmacophore analysis of existing nonpeptide endothelin antagonists. The structure-activity relationships for both the trans and the cis series of isoindolines are discussed.

Triterpene and diterpene inhibitors of pyruvate dehydrogenase kinase (PDK).

Several oximes of triterpenes with a 17-beta hydroxyl and abietane derivatives are inhibitors of pyruvate dehydrogenase kinase (PDK) activity. The oxime 12 and dehydroabietyl amine 2 exhibit a blood glucose lowering effect in the diabetic ob/ob mouse after a single oral dose of 100 micromol/kg. However, the mechanism of the blood glucose lowering effect is likely unrelated to PDK inhibition.

Characterization of a potent and selective endothelin-B receptor antagonist, IRL 2500

Summary: IRL 2500 [N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)-alanyl-L-tryptophan] inhibited the binding of [125I]-endothelin-l (ET-1) to human ETB (IC50 1.3 ± 0.2 nM) and ETA (IC50 94 ± 3 nM) receptors expressed in transfected Chinese hamster ovary (CHO) cells. In in vitro studies, IRL 2500 inhibited the sarafo-toxin S6c (STX6c)-mediated contraction of the dog saphenous vein (pKb 7.77) and the STX6c-induced relaxation of the preconstricted rabbit mesenteric artery (pKb 6.92). In the anesthetized rat, IRL 2500 (10 mg/kg, i.v.) inhibited the initial transient decrease in mean arterial pressure (MAP) induced by the ETB-selective agonist IRL 1620 (0.5 nmol/kg, i.v.). IRL 2500 also attenuated the IRL 1620-mediated increase in renal vascular resistance (RVR) in the anesthetized rat. Therefore, IRL 2500 is a potent and selective ETB receptor antagonist that can be used to delineate ET responses mediated by the ETB receptor.

CGS 27830, a potent nonpeptide endothelin receptor antagonist

Abstract Treatment of the dihydropyridine carboxylic acid 1 with EDCI produced a diastereomeric mixture of chemically stable anhydrides. The meso-isomer, CGS 27830, was isolated by crystallization and found to be a potent (16 nM) endothelin receptor antagonist for the ETA receptor subtype.

Characterization of CGS 31447, a potent and nonpeptidic endothelin-converting enzyme inhibitor.

Optimization of an aminophosphonic acid series of compounds for inhibition of endothelin-converting enzyme (ECE) has led to the discovery of CGS 31447. This compound reversibly inhibited the activity of recombinant human ECE-1 with an IC50 value of 21 nM. The effect of CGS 31447 was not due to nonspecific chelation of the zinc ion at the catalytic center of ECE-1 by the phosphonic acid of the inhibitor. Determination of kinetic parameters of ECE-1 in the presence of 5-15 nM CGS 31447 revealed the competitive nature of the compound; a K1 of 7 nM was obtained. CGS 31447 infused at concentrations of 0.01, 0.1, and 1.0 microM inhibited the mean increase in big ET-1-induced pressor responses in isolated and perfused rat kidneys by 7, 39, and 68%, respectively, compared with the controls. These results demonstrate that CGS 31447 is a potent, reversible, and competitive inhibitor of ECE-1.

Delineation of endothelin receptor subtypes in rat and rabbit aortas

Summary: The receptor subtypes mediating tension responses to endothelin-1 (ET-1) in isolated rat and rabbit aortic preparations were examined with various ET receptor antagonists. In the presence of 3 u,M IRL 2500 (an ETB-selective antagonist), SB 209670 (an ETA/ETB antagonist) induced monophasic inhibitions of the ET-1 dose-response curves of both rat (pKB 9.1) and rabbit aortas (pKB 8.9). In the presence of IRL 2500, PD 156707 (an ETA antagonist) also caused a similar monophasic inhibition of the agonist-induced dose-response curve of the rat aorta (pKB 7.7) but produced a biphasic inhibition of the curve obtained with the rabbit aorta. PD 156707, however, produced monophasic inhibitions of the ET-1-induced dose-response curve of rabbit aortas pretreated either with BQ 788 (an ETB-selective antagonist) or desensitized with sarafotoxin S6c (an ETB-selective agonist). The receptor subtypes mediating the contractile responses to ET-1 were further characterized by examining the effects of the antagonists on the binding of [125I]ET-1 to these two tissues. In the presence of 1 nM IRL 2500, SB 209670 displaced [125I]ET-1 binding in both rat and rabbit aortic membrane preparations in a monophasic manner, with similar potencies (IC50 1.2–1.6 nM). Similar results were also obtained with PD 156707 in rat aortic membrane (IC50 0.27 nM). In contrast, the data obtained with PD 156707 using rabbit aortic membrane were best-fitted with a two-site model (site 1, IC50 0.21 nM, 67% of Bmax; site 2, 100 nM and 33%, respectively). Therefore, the constrictor response to ET-1 in the rat aorta is mediated exclusively by the ETA receptor, whereas that in the rabbit aorta is additionally mediated by an ETB receptor subtype that is sensitive to SB 209670 and BQ 788 but insensitive to IRL 2500.

Effects of pH and anion substitution on magnesium accumulation in rabbit aortic smooth muscle.

The effects of anion substitution, pH and extracellular Mg2+ concentration on 28Mg accumulation were examined in rabbit aortic smooth muscle. Accumulation of 28Mg (expressed as a 28Mg/Mg2+ ratio) was not changed when the concentration of added, nonradioactive MgCl2 was increased from 1.5 to 15.0 mM. The 28Mg efflux rate was increased by added MgCl2 (0.15, 0.5 or 1.5 mM) in a dose-related manner after a similar delay of 5-10 min. Addition of 1.5 mM MgCl2, MgSO4 or magnesium aspartate hydrochloride enhanced 28Mg efflux and inhibited accumulation of 28Mg to the same extent. An increase or decrease in extracellular pH correspondingly increased or decreased 28Mg accumulation. However, the 28Mg efflux rate was not altered when extracellular pH was decreased. Efflux of 28Mg was increased by added 1.5 mM MgCl2 at pH 7.4 but not at pH 5.8. Thus, the net uptake of Mg2+ appears to be proportional to the concentration of extracellular Mg2+ in rabbit aorta. Low external pH decreases 28Mg retention in rabbit aorta by inhibiting the uptake of 28Mg rather than by increasing 28Mg efflux. Effects of added Mg2+ on transmembrane movements of 28Mg are not altered by changes in the associated anion. Extracellular Mg2+ appears to enter the cell and exchange with an intracellularly located pool of 28Mg in the same manner, regardless of whether the accompanying anion is sulfate, chloride or monoaspartate hydrochloride.

Cellular Mg ++ Accumulation is Altered by Extracellular Na + and Directly Affects Agonist-Induced Mobilization of Ca ++ in Vascular Smooth Muscle

Effects of altered Na+, Ca++ and Mg++ concentrations on 45Ca and 28Mg distribution and binding as well as of changes in cellular Mg++ on mobilization of Ca++ by added norepinephrine (NE) were examined in the rabbit aortic media-intimal layer. Uptake of 45Ca at cellular high affinity sites was decreased by Mg++ much more than 28Mg uptake was altered by Ca++. Substitution of Na+ affects 45Ca uptake primarily at extracellular (La( )-accessible) binding sites. Muscles were pre-loaded with Mg++ by incubation in a low-Na+ solution (75% Na+ replaced isosmotically with sucrose) for 30 min followed by a 90 min exposure to a similar solution also containing 15 mM MgCl2. These tissues, upon examination in normal (154 mM) Na(+)-containing solution, indicated decreased retention of that cellular, high-affinity Ca++ fraction important for NE-induced contractile response. Accordingly, release of 45Ca from this site and associated tension responses to added NE were attenuated in these muscles. These results suggest that variations in extracellular Na+ concentration modulate binding and subsequent mobilization of activator Ca++ by agonists through alterations in cellular Mg++ content in vascular smooth muscle.

Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 6. 4-substituted 3-pyridinylalkanoic acids.

Abstract (3-Pyridinyl)alkanoic acids substituted at the 4-position with an (arylsulfonamido)alkyl group were synthesized and found to behave as platelet thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs). The compounds behaved as agonists at the vascular receptor for thromboxane A2.