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Conning Towers-Nautilus Park, CT, United States

D'Angelo G.,Georgia Regents University | D'Angelo G.,Institutes for Pharmaceutical Discovery | Loria A.S.,Georgia Regents University | Pollock D.M.,Georgia Regents University | Pollock J.S.,Georgia Regents University
Hypertension | Year: 2010

Experiments were designed to test the hypothesis that endothelin (ET) and/or reactive oxygen species contribute to the pressor response induced by acute air jet stress in normotensive Dahl salt-sensitive rats maintained on a normal salt diet (prehypertensive). Mean arterial pressure was chronically monitored by telemetry before and after 3-day treatment with the free radical scavenger 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (Tempol) or ET receptor antagonists ABT-627 (ET A antagonist) or A-182086 (ET A/B antagonist) supplied in the drinking water. Rats were restrained and subjected to pulsatile air jet stress (3 minutes). Plasma samples at baseline and during acute stress were analyzed for 8-isoprostane (measure of reactive oxygen species production) and ET. Neither Tempol nor ET receptor antagonist treatment had an effect on baseline mean arterial pressure or plasma 8-isoprostane. The pressor response to acute stress was accompanied by significant increases in plasma 8-isoprostane and ET. Tempol significantly reduced both the total pressor response (area under the curve) and the stress-mediated increase in plasma 8-isoprostane; conversely, Tempol had no effect on the stress-induced increase in plasma ET. Combined ETA/B antagonism, but not selective ETA receptor blockade, similarly suppressed the pressor response to stress and stress-mediated rise in 8-isoprostane. Together these results indicate that reactive oxygen species contribute to the pressor response to acute air jet stress. Furthermore, the increase in reactive oxygen species occurs downstream of ETB receptor activation. © 2010 American Heart Association, Inc.


Zhang M.,Institutes for Pharmaceutical Discovery | Jagdmann Jr. G.E.,Institutes for Pharmaceutical Discovery | Zandt M.V.,Institutes for Pharmaceutical Discovery | Sheeler R.,Institutes for Pharmaceutical Discovery | And 2 more authors.
Journal of Natural Products | Year: 2013

The monoglucuronides and sulfates of epicatechin, 3′- Omethylepicatechin, and 4′-O-methylepicatechin, respectively, were synthesized as authentic bioanalytical standards. Reversed-phase HPLC methods capable of baseline separation of the glucuronides and sulfates have been developed. Both the epicatechin glucuronides and sulfates were stable in the solid state when stored under ambient conditions and in aqueous solution when stored refrigerated. These results should prove invaluable to the research community as analytical standards as well as in future studies of the biological and pharmacological effects of epicatechin in humans. © 2013 American Chemical Society and American Society of Pharmacognosy.


Zhang M.,Institutes for Pharmaceutical Discovery | Erik Jagdmann Jr. G.,Institutes for Pharmaceutical Discovery | Van Zandt M.,Institutes for Pharmaceutical Discovery | Beckett P.,Institutes for Pharmaceutical Discovery | Schroeter H.,MARS Symbioscience
Tetrahedron Asymmetry | Year: 2013

Ten orthogonally protected (-)-epicatechin and 3′- or 4′-O-methyl-(-)-epicatechin derivatives were prepared in a regiospecific and enantioselective manner. For each orthogonally protected (-)-epicatechin derivative, one specific phenolic hydroxyl was protected with a methoxymethyl (MOM) or p-methoxybenyzl (PMB) group and the remainder were protected as benzyl ethers. These uniquely protected (-)-epicatechin derivatives were designed to facilitate the regiospecific installation of a glucuronic acid or sulfate unit onto (-)-epicatechin after selective removal of the MOM or PMB protecting group to provide authentic standards of (-)-epicatechin glucuronides and sulfates. © 2013 Elsevier Ltd. All rights reserved.


Golebiowski A.,Institutes for Pharmaceutical Discovery | Paul Beckett R.,Institutes for Pharmaceutical Discovery | Van Zandt M.,Institutes for Pharmaceutical Discovery | Ji M.K.,Institutes for Pharmaceutical Discovery | And 11 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

Substitution at the alpha center of the known human arginase inhibitor 2-amino-6-boronohexanoic acid (ABH) is acceptable in the active site pockets of both human arginase I and arginase II. In particular, substituents with a tertiary amine linked via a two carbon chain show improved inhibitory potency for both enzyme isoforms. This potency improvement can be rationalized by X-ray crystallography, which shows a water-mediated contact between the basic nitrogen and the carboxylic acid side chain of Asp200, which is situated at the mouth of the active site pocket of arginase II (Asp181 in arginase I). We believe that this is the first literature report of compounds with improved arginase inhibitory activity, relative to ABH, and represents a promising starting point for further optimization of in vitro potency and the identification of better tool molecules for in vivo investigations of the potential pathophysiological roles of arginases. © 2013 Elsevier Ltd. All rights reserved.


Golebiowski A.,Institutes for Pharmaceutical Discovery | Whitehouse D.,Institutes for Pharmaceutical Discovery | Beckett R.P.,Institutes for Pharmaceutical Discovery | Van Zandt M.,Institutes for Pharmaceutical Discovery | And 16 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

The Ugi reaction has been successfully applied to the synthesis of novel arginase inhibitors. In an effort to decrease conformational flexibility of the previously reported series of 2-amino-6-boronohexanoic acid (ABH) analogs 1, we designed and synthesized a series of compounds, 2, in which a piperidine ring is linked directly to a quaternary amino acid center. Further improvement of in vitro activity was achieved by adding two carbon bridge in the piperidine ring, that is, tropane analogs 11. These improvements in activity are rationalized by X-ray crystallography analysis, which show that the tropane ring nitrogen atom moves into direct contact with Asp202 (arginase II numbering). The synthetic routes described here enabled the design of novel arginase inhibitors with improved potency and markedly different physico-chemical properties compared to ABH. Compound 11c represents the most in vitro active arginase inhibitor reported to date. © 2013 Elsevier Ltd. All rights reserved.

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