Selective Endothelin A Receptor Antagonists. 4. Discovery and Structure−Activity Relationships of Stilbene Acid and Alcohol Derivatives

Astles, Peter C.; Brown, Thomas J.; Halley, Frank; Handscombe, Caroline M.; Harris, Neil V.; McCarthy, Clive; McLay, Iain M.; Lockey, Peter; Majid, Tahir; Porter, Barry; Roach, A. G.; Smith, Christopher; Walsh, R. J. A.

doi:10.1021/jm970847e

Cited by 15 publications

(10 citation statements)

References 26 publications

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“…Endothelin receptor antagonists are useful therapeutic agents which are being developed for possible indications in congestive heart failure, hypertension, and some other areas. Extensive work in medicinal chemistry has been reported in the literature . Practical syntheses of some compounds in development were also described .…”

Section: Introductionmentioning

confidence: 99%

“…Practical syntheses of some compounds in development were also described . In this paper, we report a practical, concise synthesis of one of the endothelin receptor antagonists which is under development jointly by Merck and Banyu 1a. The objective of this work was to develop an efficient, safe, cost-effective, and environmentally friendly synthesis of this compound suitable for scale-up so that kilogram quantities of this drug candidate could be made via this chemistry for safety assessment and clinical studies.…”

Section: Introductionmentioning

confidence: 99%

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Practical Asymmetric Synthesis of an Endothelin Receptor Antagonist

Song¹,

Zhao²,

Desmond³

et al. 1999

J. Org. Chem.

100

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An efficient, practical, asymmetric synthesis of the endothelin receptor antagonist 1 is reported.The key pyridine-fused cyclopentane ring bearing three consecutive chiral centers was constructed by first an auxiliary induced asymmetric conjugate addition of the bottom aryllithium from 19 to an unsaturated ester 21 in high diastereoselectivity. After a highly diastereoselective addition of the top aryl Grignard reagent to the aldehyde 22, the alcohol product then underwent a stereospecific intramolecular alkylation of the ester enolate by the phosphate of the alcohol, resulting in the desired trans-trans relative stereochemistry on the cyclopentane ring. The two key chiral centers that set the chirality of the molecule were both induced from cis-1-amino-2-indanol-derived chiral auxiliaries, one in the conjugate addition reaction, the other in setting the chiral center of the bottom side chain via chiral alkylation of an enolate. Oxidation of the primary alcohol to the carboxylic acid in the bottom side chain was carried out with the newly developed TEMPO/bleachcatalyzed oxidation by sodium chlorite (NaClO 2 ) or chromium oxide catalyzed oxidation by periodic acid. The overall process has been run successfully to make multikilograms of the drug in high purity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Practical Asymmetric Synthesis of an Endothelin Receptor Antagonist

Song¹,

Zhao²,

Desmond³

et al. 1999

J. Org. Chem.

100

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“…This interaction would give a compact molecular arrangement of the analogue and would jut out the Glu 10 carboxylic function that appears to be essential for ET A , as suggested by the complete loss of activity following its amidation (compound 19). Also, accordingly, previous studies reported that specific ET A receptor antagonists require, at the receptor level, an interaction with a putative cationic site surrounded by a hydrophobic environment (Astles et al, 1998a, b). Thus, the negative charge of Glu 10 would probably interact directly with this putative cationic site found on ET A receptors.…”

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confidence: 93%

Development of agonists of endothelin‐1 exhibiting selectivity towards ET_A receptors

Langlois¹,

Létourneau²,

Lampron³

et al. 2003

British J Pharmacology

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1 Endothelin-1 (ET-1) is a bicyclic 21-amino-acid peptide causing a potent and sustained vasoconstriction, mainly through the ET A receptor subtype. So far, no selective ET A agonists are described in the literature. 2 A series of truncated and chemically modified ET-1 analogues were obtained through solid-phase peptide synthesis and their biological activity was assessed on rat thoracic aorta rings (ET A receptors) and guinea-pig lung parenchyma strips (ET B receptors). 3 Structure -activity studies led to the identification of ET-1 fragments exhibiting an ET A selective agonistic activity. 21 ]ET-1(9 -21), showed a selective ET A activity (EC 50 : 3.0 Â 10 À6 M). None of the numerous analogues of the series exhibited substantial effects in the guinea-pig lung parenchyma bioassay. 5 Thus, this study describes the first compounds showing a significant bioactivity in an ET A pharmacological preparation while being inactive in an ET B paradigm. They show that the ET-1 pharmacophores, responsible for the ET A -mediated actions, are located within the 9 -21 segment of the molecule. Moreover, the bicyclic structure of ET-1 does not appear as essential for the ET A -related vasoconstriction. Results also suggest that the positive charge of the Lys 9 side chain participates in an intramolecular ionic bond with the carboxylate function of Asp 18 .

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“…2,[5][6][7][15][16][17] In addition, many of the existing synthetic methods suffer from certain limitations with respect to yield, reaction conditions and toxicity. In particular, the formylations of 6, performed under strongly basic conditions, usually lead to 1 in rather low yields.…”

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confidence: 99%

Reaction of benzal bromides in water/dioxane system for easy access to benzaldehydes and 2-formylbenzonitriles (2-cyanobenzaldehydes)

Mola¹,

Caruso²,

Caprariis³

et al. 2016

Arkivoc

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ARKAT-USA, Inc.However, 2-formylbenzonitriles are not cheap compounds and to our knowledge relatively few methodologies which describe their synthesis have been reported (Figure 2). 2,[5][6][7][15][16][17] In addition, many of the existing synthetic methods suffer from certain limitations with respect to yield, reaction conditions and toxicity. In particular, the formylations of 6, performed under strongly basic conditions, usually lead to 1 in rather low yields. 2,18 Similar disappointing results are obtained in the reaction of 8 with the toxic CuCN. 2,19 On the other hand, the transformation of gem-dihalo compounds (benzal halides) into benzaldehydes is quite a common method. [20][21][22][23][24][25][26][27][28][29][30] In this case solvolytic displacement of halogen with successive replacement by hydroxyl followed by formal loss of HBr to generate the corresponding aldehyde, is favored by resonance stabilization offered by the aromatic ring. 29 Figure 2. Common approaches to 2-formylbenzonitriles.Hydrolysis of the benzal halides to the corresponding aldehydes is often conducted in the presence of strong acids (e.g., 95% H2SO4) or strong bases (aq. NaOH) at high temperatures, [25][26] conditions too harsh for the synthesis of 2-formylbenzonitriles, Therefore, the transformation of benzal halides 7 into 2-formylbenzonitriles have been reported under milder conditions only in the presence of the rather expensive AgNO3, used in large excess (> 3 eq.), 5-7 with severe limitations concerning the scale of the synthetic procedure, the necessity of additional tedious purification operations and eventual metal contamination. In our ongoing project on large-scale reaction of 2-formylbenzonitriles, we came across these problems and we realized that not much attention has been devoted to the development of simple and effective methods for the synthesis of these valuable aldehydes. Thus, in this article, we have reconsidered the reactivity of benzal bromides 7, developing a convenient approach to 2-formylbenzonitriles, and then we have extended the method to the synthesis of other model benzaldehydes.

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Selective Endothelin A Receptor Antagonists. 4. Discovery and Structure−Activity Relationships of Stilbene Acid and Alcohol Derivatives

Cited by 15 publications

References 26 publications

Practical Asymmetric Synthesis of an Endothelin Receptor Antagonist

Practical Asymmetric Synthesis of an Endothelin Receptor Antagonist

Development of agonists of endothelin‐1 exhibiting selectivity towards ET_A receptors

Reaction of benzal bromides in water/dioxane system for easy access to benzaldehydes and 2-formylbenzonitriles (2-cyanobenzaldehydes)

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Selective Endothelin A Receptor Antagonists. 4. Discovery and Structure−Activity Relationships of Stilbene Acid and Alcohol Derivatives

Cited by 15 publications

References 26 publications

Practical Asymmetric Synthesis of an Endothelin Receptor Antagonist

Practical Asymmetric Synthesis of an Endothelin Receptor Antagonist

Development of agonists of endothelin‐1 exhibiting selectivity towards ETA receptors

Reaction of benzal bromides in water/dioxane system for easy access to benzaldehydes and 2-formylbenzonitriles (2-cyanobenzaldehydes)

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Development of agonists of endothelin‐1 exhibiting selectivity towards ET_A receptors