Discovery and Synthesis of (S)-3-[2-(3,4-Dimethoxyphenyl)ethoxy]-2- (4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic Acid (LU 302872), a Novel Orally Active Mixed ETA/ETB Receptor Antagonist

Amberg, Willi; Hergenröder, Stefan; Hillen, Heinz; Jansen, Rolf; Kettschau, Georg; Kling, Andreas; Klinge, D. E.; Raschack, Manfred; Riechers, Hartmut; Unger, Liliane

doi:10.1021/jm9910425

Cited by 37 publications

(11 citation statements)

References 17 publications

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“…(13, I) [72] exhibited higher selectivity for ET A (Ki, ET A = 7.4 nM, ET B = 1200 nM). Similar effect was also observed [73,74] by simply varying the alkoxy substituent at the β-carbon, thereby making it possible to get compounds ranging from those that were non-specific to ones that were highly ET A specific; Fig. (13).…”

Section: Sulfonamide Antagonistssupporting

confidence: 67%

Endothelin Receptor Antagonists - An Overview

Dasgupta¹,

Mukherjee²,

Gangadhar³

2002

CMC

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In thirteen years since the appearance of Endothelin (ET) on the international scene, possibility of its involvement in a variety of diseases has attracted the attention of medicinal chemists in search of novel therapeutics for various cardiovascular diseases (CVDs). Discovery of pharmaceutical agents which either block the generation of ET from its precursor or antagonize its binding to cellular receptor, should not only provide means to assess the physiological role of ET, but lead to useful therapy for conditions associated with altered production or responsiveness to ET. In this review article, we have attempted to present in a classified format, the kaleidoscope of ET receptor antagonists that have emerged through structure activity relationship studies using the parent peptide as well as from screening of various compound libraries. By all indications, the variety and range of small molecules that are currently under investigation continues to open up newer opportunities and lures fresh groups of scientists into this research arena. Presently a number of these compounds are in the clinics, being evaluated for their beneficial effects in a range of human pathologies such as essential hypertension and chronic heart failure.

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Section: Sulfonamide Antagonistssupporting

confidence: 67%

Endothelin Receptor Antagonists - An Overview

Dasgupta¹,

Mukherjee²,

Gangadhar³

2002

CMC

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“…Presumably these findings result from the loss of the proinflammatory and profibrotic effects of ET-1, the expression of which is greatly enhanced in the scar. 15,18 Rats treated later (10 days) after MI with LU did not have impaired scar healing but nevertheless had more ventricular dilatation 100 days after MI. These results differ from those of Fraccarollo et al 12 with bosentan started 3 hours after MI and differ from all other studies evaluating ET receptor antagonists started later after MI, either selective ET A 9 -11 or nonselective ET A and ET B 10,11,13 receptor antagonists.…”

Section: Nguyen Et Al Timing Of Et Antagonism In Postinfarction Rat 2079mentioning

confidence: 97%

“…The half-life is 2 hours. 18 The efficacy of ET B receptor blockade was verified by evaluating the effects of injections of increasing doses of the ET B receptor-selective agonist BQ3020, 19 0.01 to 1 nmol/kg (Sigma), on mean arterial pressure of anesthetized rats 2 weeks after either sham operation (nϭ13) or MI (nϭ12). The BQ3020 was prepared in PBS at pH 7.4.…”

Section: Pharmacological Interventionsmentioning

confidence: 99%

Long-Term Effects of Nonselective Endothelin A and B Receptor Antagonism in Postinfarction Rat

et al. 2001

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Background-Some controversy exists as to the effects of endothelin (ET) receptor antagonism on long-term post-myocardial infarction (MI) evolution, particularly as it relates to the timing of the intervention after MI (Ͻ24 hours versus 10 days). Methods and Results-Sham rats and rats surviving an acute MI for Ͼ20 hours (nϭ301) were assigned to treatment with saline or the nonselective ET A and ET B receptor antagonist LU 420627 (LU) started Ͻ24 hours (early) or 10 days (late) after MI and continued for 100 days. Long-term LU treatment led to increased mortality of rats with large MI, regardless of the timing of initiation of therapy. Early initiation of LU reduced survival from 61% to 16% (PϽ0.001 versus untreated), and later initiation reduced survival to 36% (Pϭ0.012 versus untreated and PϽ0.001 versus early initiation). Early initiation of LU led to scar thinning, further left ventricular (LV) dilatation, LV dysfunction, and an excessive rise in right ventricular systolic pressure. Later initiation of LU did not modify scar formation but resulted in LV dilatation and dysfunction compared with the untreated group. Cardiac fibrosis tended to increase in the LU-treated MI groups. LU in the sham group reduced cardiac endothelial constitutive nitric oxide synthase but did not modify the changes that occurred with a large MI. Conclusions-The use of the nonselective ET A and ET B receptor antagonist LU results in reduced survival, ventricular dilatation, and dysfunction whether started early or late after MI. Early initiation of LU resulted in scar expansion and a particularly unfavorable outcome.

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“…The (S)-enantiomer of the latter compound is a key intermediate for the synthesis of ET receptor antagonists BSF 420627, BSF 302146 and LU 135252 (Darusentan). [17] Since the large-scale industrial synthesis of (S)-9 is based on resolution of the racemate by crystallization, [18] recycling of the undesired (R)-stereoisomer by racemization is highly desirable. However, chemical racemization methods based on acid-or base-catalysis failed: depending on the reaction conditions, elimination of methanol (to form 3,3-diphenylpyruvic acid) or C-C bond cleavage to form benzophenone and a C2 fragment (presumably glyoxylic or hydroxyacetic acid) are the main degradation pathways.…”

Section: Microorganismmentioning

confidence: 99%

Biocatalytic Racemization of (Hetero)Aryl‐aliphatic α‐Hydroxycarboxylic Acids by Lactobacillus spp. Proceeds via an Oxidation–Reduction Sequence

et al. 2006

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The biocatalytic racemization of a range of (hetero)aryl-and (di)aryl-aliphatic α-hydroxycarboxylic acids has been achieved by using whole resting cells of Lactobacillus spp. The essentially mild (physiological) reaction conditions ensure the suppression of undesired side reactions, such as elimination, decomposition or condensation. Cofactor/inhibitor studies using a cell-free extract of Lactobacillus paracasei DSM 20207 reveal that the addition of redox cofactors

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Discovery and Synthesis of (S)-3-[2-(3,4-Dimethoxyphenyl)ethoxy]-2- (4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic Acid (LU 302872), a Novel Orally Active Mixed ET_A/ET_B Receptor Antagonist

Cited by 37 publications

References 17 publications

Endothelin Receptor Antagonists - An Overview

Endothelin Receptor Antagonists - An Overview

Long-Term Effects of Nonselective Endothelin A and B Receptor Antagonism in Postinfarction Rat

Biocatalytic Racemization of (Hetero)Aryl‐aliphatic α‐Hydroxycarboxylic Acids by Lactobacillus spp. Proceeds via an Oxidation–Reduction Sequence

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