Development of Dual-Acting Agents for Thromboxane Receptor Antagonism and Thromboxane Synthase Inhibition. 3. Synthesis and Biological Activities of Oxazolecarboxamide-Substituted ω-Phenyl-ω-(3-pyridyl)alkenoic Acid Derivatives and Related Compounds

Takeuchi, Kumiko; Kohn, Todd J.; True, Timothy A.; Mais, Dale E.; Wikel, James H.; Utterback, Barbara G.; Wyss, V; Jakubowski, Joseph A.

doi:10.1021/jm980173n

Cited by 10 publications

(9 citation statements)

References 34 publications

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“…jpet.aspetjournals.org oped, ranging in effectiveness within the concentrations of 10 Ϫ4 to 10 Ϫ8 M, have not proven clinically successful (Boehm et al, 1996;Moncada et al, 1977;Needleman et al, 1977). A recent addition to this group of drugs has been made with the development of substituted -phenyl--(3-pyridyl) alkenoic acids (Takeuchi et al, 1998). These drugs were shown to be as effective as TRAs with an IC 50 of 55 ϫ 10 Ϫ9 M. The compounds were found active in washed platelet suspensions and in ex vivo models, but were less active on platelet-rich plasma, possibly due to plasma binding or metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, proper management of thromboxane-mediated disease is desirable at the level of thromboxane (synthesis and/or receptor action), as this leaves the beneficial prostaglandins in place (Bunting et al, 1983). Recently, this approach has identified a new class of compounds, oxazolecarboxamide-substituted alkenoic acids with dual TSI/TRA activities (Takeuchi et al, 1998).…”

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confidence: 99%

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A New Family of Thromboxane Receptor Antagonists with Secondary Thromboxane Synthase Inhibition

Pace-Asciak

Reynaud²,

Demin³

et al. 2002

The Journal of Pharmacology and Experimental Therapeutics

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We report herein a novel class of thromboxane receptor (TP receptor) antagonists modeled on unstable natural lipids that we identified several years ago, the hepoxilins. These antagonists have been rendered chemically and biologically more stable than the natural compounds through structural modification by chemical synthesis. We demonstrate that the analogs inhibit the aggregation of human platelets in vitro evoked by the thromboxane receptor agonists,-heptenoic acid) and U46619 (9,11-dideoxy-9␣,11␣-methanoepoxy-prosta-5Z,13E-dien-1-oic acid). The most potent of the analogs described, PBT-3 [10(S)-hydroxy-11,12-cyclopropyl-eicosa-5Z,8Z,14Z-trienoic acid methyl ester], has an IC 50 versus aggregation by I-BOP ϭ 0.6 ϫ 10 Ϫ7 M and versus U46619 ϭ 7 ϫ 10 Ϫ7 M, representing one of the most potent anti-aggregating substances so far described. PBT-3 also inhibits thromboxane formation and aggregation evoked by collagen with an IC 50 ϭ 8 ϫ 10 Ϫ7 M. Other PBT (hepoxilin cyclopropane) analogs so far tested were 5-to 10-fold less active, and the native hepoxilins were about 500-fold less active. Neither PBT-3 nor the other analogs inhibited 12-lipoxygenase, phospholipase A 2 , or cyclooxygenase 1 or 2, and weakly stimulated adenyl cyclase (threshold stimulation at 10 Ϫ7 M and little selectivity for each of the PBT compounds). TP antagonism by PBT-3 was further demonstrated in receptor binding studies through use of 125

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

A New Family of Thromboxane Receptor Antagonists with Secondary Thromboxane Synthase Inhibition

Pace-Asciak

Reynaud²,

Demin³

et al. 2002

The Journal of Pharmacology and Experimental Therapeutics

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“…Compound 11h was prepared in a straightforward manner by heating bromo-methylcyclohexane in ethylene glycol, under strong basic conditions (Scheme 5) [57,58].…”

Section: Chemistrymentioning

confidence: 99%

Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure–activity relationship (SAR) studies

Nuzzi

Fiasella

Ortega

et al. 2016

European Journal of Medicinal Chemistry

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4-Cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate (3b) is a potent, selective and systemically active inhibitor of intracellular NAAA activity, which produces profound anti-inflammatory effects in animal models. In the present work, we describe structure-activity relationship (SAR) studies on 3-aminoazetidin-2-one derivatives, which have led to the identification of 3b, and expand these studies to elucidate the principal structural and stereochemical features needed to achieve effective NAAA inhibition. Investigations on the influence of the substitution at the β-position of the 2-oxo-3-azetidinyl ring as well as on the effect of size and shape of the carbamic acid ester side chain led to the discovery of 3ak, a novel inhibitor of human NAAA that shows an improved physicochemical and drug-like profile relative to 3b. This favourable profile, along with the structural diversity of the carbamic acid chain of 3b, identify this compound as a promising new tool to investigate the potential of NAAA inhibitors as therapeutic agents for the treatment of pain and inflammation.

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“…While exploring derivatives of 2 , we found that 2-phenyl-oxazole-4-carboxamide derivative 3 was also active against M. tuberculosis . 2-Phenyl-oxazole-4-carboxamides are known inhibitors of histone deacetylase,14 Stat3,15 phosphodiesterase,16 phosphatase,17 thromboxane synthase,18 and kinase proteins,19 and known activators of cellular caspase activity 20. We synthesized derivatives of 3 to identify a more potent anti-tuberculosis agent 13.…”

Section: Introductionmentioning

confidence: 99%

N-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide as a New Scaffold that Provides Rapid Access to Antimicrotubule Agents: Synthesis and Evaluation of Antiproliferative Activity Against Select Cancer Cell Lines

et al. 2010

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A series of N- ((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamides was synthesized by coppercatalyzed azide-alkyne cycloaddition (CuAAC) and afforded inhibitors of cancer cell growth. For example, compound 13e had an IC 50 of 46 nM against MCF-7 human breast tumor cells. Structure-activity relationship (SAR) studies demonstrated that (i) meta-phenoxy substitution of the N-1-benzyl group is important for antiproliferative activity and (ii) a variety of heterocyclic substitutions for the aryl group of the arylamide are tolerated. In silico COMPARE analysis of antiproliferative activity against the NCI-60 human tumor cell line panel revealed a correlation to clinically useful antimicrotubule agents such as paclitaxel and vincristine. This in silico correlation was supported by (i) in vitro inhibition of tubulin polymerization, (ii) G 2 /M-phase arrest in HeLa cells as assessed by flow cytometry, and (iii) perturbation of normal microtubule activity in HeLa cells as observed by confocal microscopy. The results demonstrate that N- ((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide is a readily accessible small molecule scaffold for compounds that inhibit tubulin polymerization and tumor cell growth.

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Development of Dual-Acting Agents for Thromboxane Receptor Antagonism and Thromboxane Synthase Inhibition. 3. Synthesis and Biological Activities of Oxazolecarboxamide-Substituted ω-Phenyl-ω-(3-pyridyl)alkenoic Acid Derivatives and Related Compounds

Cited by 10 publications

References 34 publications

A New Family of Thromboxane Receptor Antagonists with Secondary Thromboxane Synthase Inhibition

A New Family of Thromboxane Receptor Antagonists with Secondary Thromboxane Synthase Inhibition

Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure–activity relationship (SAR) studies

N-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide as a New Scaffold that Provides Rapid Access to Antimicrotubule Agents: Synthesis and Evaluation of Antiproliferative Activity Against Select Cancer Cell Lines

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