Nonpeptide endothelin antagonists in clinical development

Wu, Changfan; Er, Decker; Gw, Holland; Pm, Brown; Fd, Stavros; Ta, Brock; Ra, Dixon

doi:10.1358/dot.2001.37.7.844187

Cited by 21 publications

(7 citation statements)

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“…Selectivity of 7z was in the lead (441000-fold) compared with other ET A selective compounds such as BMS193884, atrasentan, Cl-1034, Z1611 and sitaxsentan (going from 1400- to 7000-fold). Except for peptides BQ123, TAK-044, and the iv drug tezosentan, most small molecule antagonists are generally >50% orally available, with 7z being close to 100% in rats and 80% in humans 1c8 Comparisons of 7z with Lead Endothelin Antagonists generic name/codeET A IC 50 (nM)ET A K i (nM)selectivity for ET A over ET B (fold)oral availability (%) t 1/2 (h)references BQ123 22 818 peptide 35 bosentan 6.5 53 30−80 36 tezosentan 23 56 iv drug 0.13 37 atrasentan 0.31 0.034 2000 60, rat 3.5 38 darusentan 6 60 39 enrasentan 1.1 100 60, rat 40 BMS-193884 1.4 1400 43, rat 2, rat 41 71, monkey 9, monkey J-104132 0.034 3 40, rat 42 Cl-1034 0.46 4500 77, rat 8.5, rat 43 100, dog 2.2, dog Z1611 0.2 5000 4.8 44 TAK-044 0.24 540 peptide 0.5−1 45 YM598 3.1 387 89, rat 2.5, rat 46 97, dog 7.4, dog 1 1.4 0.43 7000 50−60, rat 5.9−7.5, rat 2 90−100, dog 4−4.8, dog ∼80, human 6.46, human 7z ...…”

Section: Discussionmentioning

confidence: 99%

“…4 When administered orally at 2 mg/kg to humans (N ) 4), sitaxsentan has an AUC 0-∞ of 33.02 ( 7.08 h‚µg/mL with C max of 16.43 ( 5.86 µg/mL. The elimination halflife is 6.46 ( 1.52 h with a T max of 1.75 ( 0.96 h. 18 In a phase 2b/3 STRIDE trial in 178 pulmonary arterial hypertension patients, once a day treatment of 100 mg and 300 mg of sitaxsentan statistically significantly improved 6-min walk distance and NYHA class at 12 weeks. 6,19 Both doses resulted in significant improvements in hemodynamics in these NYHA class II-IV patients.…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

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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“…sulfadiazine, and diuretics, such as hydrochlorothiazide, have been therapeutically used for many decades. 1 Examples for recently approved drugs with a sulfonamide structure are the antihypertensive agent bosentan, 2 the antiviral HIV protease inhibitor amprenavir, 3 and the phosphodiesterase-5 inhibitor sildenafil. 4 In addition, numerous sulfonamide derivatives have been in preclinical development.…”

Section: Introductionmentioning

confidence: 99%

A New Synthesis of Sulfonamides by Aminolysis ofp-Nitrophenylsulfonates Yielding Potent and Selective Adenosine A_2BReceptor Antagonists

et al. 2006

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1-Propyl- and 1,3-dimethyl-8-p-sulfophenylxanthine (PSB-1115 and SPT) were used as starting compounds for the development of adenosine A(2B) receptor antagonists with a sulfonamide structure. Since standard reactions for sulfonamide formation failed or resulted in very low yields, we developed a new method for the preparation of sulfonamides. p-Nitrophenoxide was used as a suitable leaving group with well balanced stability-reactivity properties. A large variety of amines, including aniline, benzylamine, phenethylamine, propylamine, butylamine, 2-hydroxyethylamine, aminoacetic acid, and N-benzylpiperazine reacted with p-nitrophenoxysulfonylphenylxanthine derivatives yielding the desired sulfonamides in satisfying to very good yields. The obtained sulfonamides were much more potent at A(2B) receptors than the parent sulfonates. The most active compound of the present series was 8-[4-(4-benzylpiperazide-1-sulfonyl)phenyl]-1-propylxanthine (11, PSB-601) exhibiting a K(i) value of 3.6 nM for the human A(2B) receptor combined with high selectivity versus the other human adenosine receptor subtypes (575-fold versus A(1), 134-fold versus A(2A), and >278-fold versus A(3)).

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“…Also, sulphonamides constitute an important class of drugs, with several types of pharmacological agents possessing anticancer , antihypertensive , antiviral , and anti‐inflammatory agents. In addition, sulphonamides have been found to be powerful carbonic anhydrase and HIV protease inhibitors . Some organisms are resistant to all approved antibiotics and can only be reacted with experimental and potentially toxic drugs.…”

Section: Introductionmentioning

confidence: 99%

Novel 7‐Nitro‐1‐(Piperidin‐4‐yl)‐4,5‐Dihydro‐[1,2,4] Triazolo[4,3‐a]Quinoline‐Sulphonamide Derivatives as Antimicrobial Agents: Design, Synthesis, and Bio‐Activity

Reddy

et al. 2015

Journal of Heterocyclic Chem

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in Wiley Online Library (wileyonlinelibrary.com).In attempt to search for more potent antimicrobial agents, a series of 7-nitro-1-(piperidin-4-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-derived sulphonamides were synthesized. Their structures were established by elemental analyses, IR, and NMR ( 1 H and 13 C) spectral data. The antibacterial activity of the obtained compounds was investigated against different Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive (Bacillus subtilis and Staphylococcus aureus) bacteria and antifungal activity against two fungal strains (Aspergillus niger and Aspergillus clavatus) using disk diffusion method at various concentrations (20, 40, 60, and 80 μg/mL). The study reveals that most of the title compounds showed significant antibacterial and fungal activity when compared with their respective standards streptomycin and griseofulvin.

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Nonpeptide endothelin antagonists in clinical development

Cited by 21 publications

References 0 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

A New Synthesis of Sulfonamides by Aminolysis ofp-Nitrophenylsulfonates Yielding Potent and Selective Adenosine A_2BReceptor Antagonists

Novel 7‐Nitro‐1‐(Piperidin‐4‐yl)‐4,5‐Dihydro‐[1,2,4] Triazolo[4,3‐a]Quinoline‐Sulphonamide Derivatives as Antimicrobial Agents: Design, Synthesis, and Bio‐Activity

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Nonpeptide endothelin antagonists in clinical development

Cited by 21 publications

References 0 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

A New Synthesis of Sulfonamides by Aminolysis ofp-Nitrophenylsulfonates Yielding Potent and Selective Adenosine A2BReceptor Antagonists

Novel 7‐Nitro‐1‐(Piperidin‐4‐yl)‐4,5‐Dihydro‐[1,2,4] Triazolo[4,3‐a]Quinoline‐Sulphonamide Derivatives as Antimicrobial Agents: Design, Synthesis, and Bio‐Activity

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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

A New Synthesis of Sulfonamides by Aminolysis ofp-Nitrophenylsulfonates Yielding Potent and Selective Adenosine A_2BReceptor Antagonists