Ethenesulfonamide and ethanesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists

Harada, Hironori; Kazami, Jun‐ichi; Watanuki, Susumu; Tsuzuki, Ryuji; Sudoh, Katsumi; Fujimori, A.; Sanagi, Masanao; Orita, Masaya; Nakahara, Hideaki; Shimaya, Jun; Tsukamoto, Shin‐ichi; Tanaka, Akihiro; Yanagisawa, Isao

doi:10.1016/s0968-0896(01)00187-0

Cited by 14 publications

(2 citation statements)

References 24 publications

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“…Medicinal chemistry research has been quite successful in the endothelin area, and at least 14 lead antagonists generated from various laboratories have been evaluated preclinically or clinically. Their names/codes, potency (IC 50 , K i ), selectivity, oral availability, half-lives, and references [35][36][37][38][39][40][41][42][43][44][45][46] are listed in Table 8. Compound 7z compares very well with other lead compounds in terms of in vitro potency, selectivity, and oral availability.…”

Section: Discussionmentioning

confidence: 99%

Discovery, Modeling, and Human Pharmacokinetics ofN-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ET_ASelective, and Orally Bioavailable Endothelin Antagonist

Wu¹,

Decker²,

Blok³

et al. 2004

J. Med. Chem.

104

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Sitaxsentan (1) (Wu et al. J. Med. Chem. 1997, 40, 1690) is our first endothelin antagonist being evaluated in clinical trials. It has demonstrated biological effects in an acute hemodynamic study in CHF (Givertz et al. Circulation 2000, 101, 2922), an open-label 20-patient pulmonary hypertension trial (Barst et al. Chest 2002, 121, 1860-1868), and a 31-patient trial in essential hypertension (Calhoun et al. AHA Scientific Sessions 2000). In a phase 2b/3 pulmonary arterial hypertension trial, once a day treatment of 100 mg of sitaxsentan statistically significantly improved 6-min walk distance and NYHA class at 12 weeks (Barst et al. Am. J. Respir. Crit. Care Med. 2004, 169, 441). We have since reported on our efforts in generating follow-up compounds (Wu et al. J. Med. Chem. 1999, 42, 4485) and recently communicated that an ortho acyl group on the anilino ring enhanced oral absorption in this category of compounds (Wu et al. J. Med. Chem. 2001, 44, 1211). Here we report an expansion of this work by substituting a variety of electron-withdrawing groups at the ortho position and evaluating their effects on oral bioavailability as well as structure-activity relationships. As a result, TBC3711 (7z) was identified as our second endothelin antagonist to enter the clinic due to its good oral bioavailability (approximately 100%) in rats, high potency (ET(A) IC(50) = 0.08 nM), and optimal ET(A)/ET(B) selectivity (441 000-fold). Compound 7z has completed phase-I clinical development and was well tolerated with desirable pharmacokinetics in humans (t(1/2) = 6-7 h, oral availability > 80%).

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Section: Discussionmentioning

confidence: 99%

Discovery, Modeling, and Human Pharmacokinetics ofN-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ET_ASelective, and Orally Bioavailable Endothelin Antagonist

Wu¹,

Decker²,

Blok³

et al. 2004

J. Med. Chem.

104

View full text Add to dashboard Cite

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“…Further, introducing steric hindrance to the alkylating moiety through α-methylation resulted in decreased activity 26 . Therefore, having BW-AQ-295 with the introduction of terminal alkyl ketone groups at the R 1 and R 1′ positions, we further studied if the chloroacetamide group of BW-AQ-295 (R 2 substitution) can be replaced by other commonly used electrophiles 39–43 including acrylamide 44 , 45 , propynamide 46 , 47 , and ethensulfonamide 48 ( Table 1 ). Compared to BW-AQ-295 , the acrylamide analog BW-AQ-353 was about 15-fold less potent.…”

Section: Resultsmentioning

confidence: 99%

Upregulation of p53 through induction of MDM2 degradation: improved potency through the introduction of an alkylketone sidechain on the anthraquinone core

Tripathi

Anifowose

Wen

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Overexpression of ubiquitin ligase MDM2 causes depletion of the p53 tumour-suppressor and thus leads to cancer progression. In recent years, anthraquinone analogs have received significant attention due to their ability to downregulate MDM2, thereby promoting p53-induced apoptosis. Previously, we have developed potent anthraquinone compounds having the ability to upregulate p53 via inhibition of MDM2 in both cell culture and animal models of acute lymphocytic leukaemia. Earlier work was focussed on mechanistic work, pharmacological validation of this class of compounds in animal models, and mapping out structural space that allows for further modification and optimisation. Herein, we describe our work in optimising the substituents on the two phenol hydroxyl groups. It was found that the introduction of an alkylketone moiety led to a potent series of analogs with BW-AQ-350 being the most potent compound yet (IC 50 = 0.19 ± 0.01 µM) which exerts cytotoxicity by inducing MDM2 degradation and p53 upregulation.

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Facile Installation of 2‐Reverse Prenyl Functionality into Indoles by a Tandem N‐Alkylation–Aza‐Cope Rearrangement Reaction and Its Application in Synthesis

Chen

Fan

Zhang

et al. 2015

Chemistry A European J

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An unprecedented tandem N-alkylation-ionic aza-Cope (or Claisen) rearrangement-hydrolysis reaction of readily available indolyl bromides with enamines is described. Due to the complicated nature of the two processes, an operationally simple N-alkylation and subsequent microwave-irradiated ionic aza-Cope rearrangement-hydrolysis process has been uncovered. The tandem reaction serves as a powerful approach to the preparation of synthetically and biologically important, but challenging, 2-reverse quaternary-centered prenylated indoles with high efficiency. Notably, unusual nonaromatic 3-methylene-2,3-dihydro-1H-indole architectures, instead of aromatic indoles, are produced. Furthermore, the aza-Cope rearrangement reaction proceeds highly regioselectively to give the quaternary-centered reverse prenyl functionality, which often produces a mixture of two regioisomers by reported methods. The synthetic value of the resulting nonaromatic 3-methylene-2,3-dihydro-1H-indole architectures has been demonstrated as versatile building blocks in the efficient synthesis of structurally diverse 2-reverse prenylated indoles, such as indolines, indole-fused sultams and lactams, and the natural product bruceolline D.

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Ethenesulfonamide and ethanesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists

Cited by 14 publications

References 24 publications

Discovery, Modeling, and Human Pharmacokinetics ofN-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ET_ASelective, and Orally Bioavailable Endothelin Antagonist

Discovery, Modeling, and Human Pharmacokinetics ofN-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ET_ASelective, and Orally Bioavailable Endothelin Antagonist

Upregulation of p53 through induction of MDM2 degradation: improved potency through the introduction of an alkylketone sidechain on the anthraquinone core

Facile Installation of 2‐Reverse Prenyl Functionality into Indoles by a Tandem N‐Alkylation–Aza‐Cope Rearrangement Reaction and Its Application in Synthesis

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Ethenesulfonamide and ethanesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists

Cited by 14 publications

References 24 publications

Discovery, Modeling, and Human Pharmacokinetics ofN-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ETASelective, and Orally Bioavailable Endothelin Antagonist

Discovery, Modeling, and Human Pharmacokinetics ofN-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ETASelective, and Orally Bioavailable Endothelin Antagonist

Upregulation of p53 through induction of MDM2 degradation: improved potency through the introduction of an alkylketone sidechain on the anthraquinone core

Facile Installation of 2‐Reverse Prenyl Functionality into Indoles by a Tandem N‐Alkylation–Aza‐Cope Rearrangement Reaction and Its Application in Synthesis

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Product

Resources

About

Discovery, Modeling, and Human Pharmacokinetics ofN-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ET_ASelective, and Orally Bioavailable Endothelin Antagonist

Discovery, Modeling, and Human Pharmacokinetics ofN-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ET_ASelective, and Orally Bioavailable Endothelin Antagonist