Acyl Substitution at the Ortho Position of Anilides Enhances Oral Bioavailability of Thiophene Sulfonamides:  TBC3214, an ET_A Selective Endothelin Antagonist

Abstract

Sitaxsentan (3, TBC11251) (Wu et al. J. Med. Chem. 1997, 40, 1690) is an orally active ET(A) selective endothelin antagonist that attenuates pulmonary vascular hypertension and cardiac hypertrophy in rats (Tilton et al. Pulm. Pharmacol. Ther. 2000, 13, 87). It has demonstrated efficacy in a phase II clinical trial for congestive heart failure (Givertz et al. Circulation 2000, 101, 2922). During the discovery of 3, we observed several structure-oral bioavailability relationships. To investigate whether there is any generality in these trends, we synthesized some similar pairs of compounds in the latest series (Wu et al. J. Med. Chem. 1999, 42, 4485) and evaluated their oral properties. In both series, an acyl group at the 2-position of the anilide of these thiophene sulfonamides improved oral bioavailability. As a result of this exercise, TBC3214 (17) was identified as a sitaxsentan follow-on candidate. It is very potent (IC(50) for ET(A) = 40 pM) and highly selective for ET(A) vs ET(B) receptors (400 000-fold), with a half-life of >4 h and oral bioavailability of 25% in rats, 42% in cats, and 70% in dogs.

Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space

“…This compound fails the Ro5 on three counts, M w , clogP, and N/O count, and has a significant number of hydrogen bond donors (Table 2). Other physicochemical descriptors such as TPSA and nROT (16) are clearly also high, and therefore it is remarkable that this compound has such a high reported oral bioavailability of 60% in humans. 27 To understand the potential for IHB formation we first submitted atazanavir to a conformational search in the gas phase.…”

“…23 Similarly for antagonists of the endothelin receptor A, several compounds were predicted, by molecular modelling, to exhibit IHBs which was used to rationalise the unexpectedly higher oral bioavailability in rats. 16 The formation of an IHB can not only potentially increase the permeability of molecules across the intestinal membrane but also across the blood brain barrier. A noteworthy example includes compounds designed as antagonists against NK1.…”

ETAselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats

“…Anesthesia for the experimental procedure was affected by pentobarbital sodium (50 mg/kg ip). The selective (ETA) endothelin receptor antagonist, TBC-3214, is a next-generation sitaxsentan that has an IC50 for ETA of 40 pM and is highly selective for ETA vs. ETB (400,000-fold) (54). TBC-3214 (25 mg/kg body wt; Texas Biotechnology) was dissolved in drinking water, administered 3-5 days before surgery, and continued for the duration of the specific experimental group (i.e., 1 and 5 days or 8 wk postfistula).…”

“…TBC-3214 (25 mg/kg body wt; Texas Biotechnology) was dissolved in drinking water, administered 3-5 days before surgery, and continued for the duration of the specific experimental group (i.e., 1 and 5 days or 8 wk postfistula). This dose of TBC-3214 was selected based on the manufacturer's (Texas Biotechnology) specified oral bioavailability concentrations documented in previous in vitro studies (42,53,54). Use of this class of ETA receptor antagonist in heart failure patients was capable of improving pulmonary hemodynamics but did not affect systemic vascular resistance (for review, see Ref.…”

Synthesis and Binding Properties of New Endothelin Receptor Ligands

“…Moreover, the discovery of thiophenesulfonamides, like as sitaxsentan (TBC11251) (Fig. 1), led to potent and selective ET A receptor antagonists [6][7][8][9][10][11][12]. In this paper, continuing our researches [13][14][15] and with the aim to obtain new ET receptor ligands, we report the synthesis and binding test results of a new series of benzenesulfonamides.…”