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

Abstract

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%).

Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes

“…[1][2][3][4][5] The interest in this kind of heterocycles has spread from dye chemistry 6 to modern drug design 7 , biodiagnostics 8 , electronic and optoelectronic devices 9 , conductivity-based sensors 10 and self-assembled superstructures. 11 2-Amino-3-aroylthiophenes are agonist allosteric enhancers at the A 1 adenosine receptor.…”

“…Because the structure-based drug design program through substituted 2-aminothiophenes has been investigated broadly, up to this date there are many other research works dealing with the synthesis, pharmacology and application of thiophene-based structures in medicinal chemistry. 7,[12][13][14]36,37,51,69,100,101,[119][120][121][122][123][124][125][126][127] It is no doubt, that this area of Gewald-like thiophene derivatives exhibits the highest progress in a scope and utilization.…”

Optimizing endothelin receptor antagonist use in the management of pulmonary arterial hypertension

“…Endothelin receptor antagonists in pulmonary arterial hypertension after administration (Prod Info Letairis ® oral tablets 2007) and oral sitaxsentan reaches peak concentration within 1 to 3 hours (Wu et al 2004b).…”

A facile and environmentally benign polyethylene glycol 600-mediated method for the synthesis of densely functionalized 2-aminothiophene derivatives under ultrasonication

“…The Gewald reaction is a popular catalytic and one-pot three-component reaction between elemental sulfur, a cyanomethylene containing an electron-withdrawing group and an enolizable carbonyl compound that affords highly substituted 2-aminothiophene derivatives (12,20). Indeed, 2-aminothiophene scaffold has found wide applications from modern drug design (21,22) to dye chemistry (23,24) (Figure 1). Figure 1 shows some typical biologically active compounds containing 2-aminothiophene scaffold which can be prepared through the Gewald MCR.…”