Synthesis of novel substituted pyridines as inhibitors of endothelin coverting enzyme-1 (ECE-1)

Massa, Mark A.; Patt, William C.; Ahn, Kyunghye; Sisneros, Andre M.; Herman, Sarah B.; Doherty, Annette M.

doi:10.1016/s0960-894x(98)00375-8

Cited by 19 publications

(5 citation statements)

References 13 publications

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“…In parallel, we have also searched for agents able to selectively inhibit ECE-1 because inhibition of NEP may not always be necessary or even desirable under some pathological conditions such as asthma . Several attempts to obtain selective ECE-1 inhibitors by systematic structural modification of the dipeptidic metalloprotease inhibitor phosphoramidon , or by screening compound and natural product libraries have been reported. ,− Although moderate success has been reported occasionally, the identification of potent and selective ECE-1 inhibitors that possess sustained functional activity in vivo still remains a challenge. Consequently, the in vivo characterization of ECE inhibitors remains scarce. , …”

Section: Introductionmentioning

confidence: 99%

Potent and Selective Non-Peptidic Inhibitors of Endothelin-Converting Enzyme-1 with Sustained Duration of Action

et al. 2000

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Potent and selective non-peptidic inhibitors of human endothelin-converting enzyme-1 (ECE-1) have been designed as potential modulators of endothelin (ET-1) production in vivo. Because of its unique structural characteristics and long duration of action in vivo, the dual ECE-1 and neutral endopeptidase 24.11 (NEP) inhibitor, CGS 26303, was selected as an attractive lead for further optimization of potency and selectivity. Replacement of the P(1)' biphenyl substituent of CGS 26303 by a conformationally restricted 3-dibenzofuranyl group led to more potent and more selective ECE-1 inhibitors, such as the tetrazole 27. The remarkable effect of this P(1)' modification allowed for the first time phosphonomethylcarboxylic acids, such as 29, to display both potent (IC(50) = 22 nM) and selective (104-fold vs NEP) ECE-1 inhibition. Chemoenzymatic syntheses of the new alpha-amino acid (S)-3-dibenzofuran-3-ylalanine intermediate were developed, and improved procedures to generate substituted alpha-aminoalkylphosphonic acids were devised to support the production of various analogues. Although additional gains in intrinsic ECE-1 inhibitory potency could occasionally be achieved by addition of a P(1) side chain, these compounds (e.g. 43a) showed poor functional activity in vivo in the big ET-1 pressor test. Phosphonoalkyl dipeptides featuring 3-dibenzofuranyl groups in both the P(1)' and P(2)' positions were also very potent ECE-1 inhibitors, albeit lacking the desired selectivity against NEP. Functionally, 27and 29 were the two most efficacious compounds from this study, producing sustained inhibition of ECE-1 activity in rats, as measured by their ability to block the hypertensive effects induced by big ET-1. This profile was similar to that of a potent ET(A)/ET(B) dual receptor antagonist, SB 209670. Due to their favorable in vitro and in vivo profiles, 27 (CGS 34043) and 29 (CGS 35066) constitute new pharmacological tools useful in assessing the role of ECE-1 in pathological conditions.

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Section: Introductionmentioning

confidence: 99%

Potent and Selective Non-Peptidic Inhibitors of Endothelin-Converting Enzyme-1 with Sustained Duration of Action

et al. 2000

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“…We next turned the attention to electrophilic iodination. Iodine in the presence of sodium bicarbonate has previously been used for the introduction of iodine into pyridinols . We were pleased to find that pyridinol 7 was selectively monoiodinated in position 2 when heated with this reagent at reflux in a 1:1 mixture of water and tetrahydrofuran for 4 h. (48% isolated yield of compound 9b ).…”

Section: Resultsmentioning

confidence: 98%

Turning Pyridoxine into a Catalytic Chain-Breaking and Hydroperoxide-Decomposing Antioxidant

2013

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Vitamin B6 is involved in a variety of enzymatic transformations. Some recent findings also indicate an antioxidant role of the vitamin in biological systems. We set out to turn pyridoxine (1a) into a catalytic chain-breaking and hydroperoxide-decomposing antioxidant by replacing the 2-methyl substituent with an alkyltelluro group. Target molecules 12 and derivatives 14, 17, 18, and 20 thereof were accessed by subjecting suitably substituted 2-halopyridin-3-ols to aromatic substitution using sodium alkanetellurolates as nucleophiles and then LAH-reduction of ester groups. The novel pyridoxine compounds were found to inhibit azo-initiated peroxidation of linoleic acid an order of magnitude more efficiently than α-tocopherol in a water/chlorobenzene two-phase system containing N-acetylcysteine as a reducing agent in the aqueous phase. The most lipid-soluble pyridoxine derivative 20c was regenerable and could inhibit peroxidation for substantially longer time (>410 min) than α-tocopherol (87 min). The chalcogen-containing pyridoxines could also mimic the action of the glutathione peroxidase enzymes. Thus, compound 20a catalyzed reduction of hydrogen peroxide three times more efficiently than Ebselen in the presence of glutathione as a stoichiometric reducing agent.

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“…Stangeland et al 28 described the total synthesis of WS75624 B 14, which is a potent endothelin converting enzyme (ECE) inhibitor and potential antihypertensive agent. 29 This compound was synthesized from KA in ten steps.…”

Section: Methodsmentioning

confidence: 99%

Kojic acid in organic synthesis

Zirak¹,

Eftekhari‐Sis²

2015

Turk J Chem

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The reactions of kojic acid in organic synthesis are reviewed. The aim of this review is to cover the literature up to the end of 2014, showing the distribution of publications involving kojic acid chemistry in the synthesis of various pyrone containing compounds, pyridine and pyridone heterocycles, and also other organic compounds. First, introductory text about the preparation, biological, and industrial applications, and the chemical properties of kojic acid is given.Then its uses in organic synthesis are presented considering the reaction type.

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Synthesis of novel substituted pyridines as inhibitors of endothelin coverting enzyme-1 (ECE-1)

Cited by 19 publications

References 13 publications

Potent and Selective Non-Peptidic Inhibitors of Endothelin-Converting Enzyme-1 with Sustained Duration of Action

Potent and Selective Non-Peptidic Inhibitors of Endothelin-Converting Enzyme-1 with Sustained Duration of Action

Turning Pyridoxine into a Catalytic Chain-Breaking and Hydroperoxide-Decomposing Antioxidant

Kojic acid in organic synthesis

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