Endothelin antagonist

There are also several examples of the use of Suzuki reactions in scale-up synthesis of drug candidates. In the synthesis of CI-1034, an endothelin antagonist, a triflate,... 

T. J., Azole endothelin antagonists. 3. Using AlogP as a tool to improve absorption, J. Med Chem. 39, 982-991 (1996). 

Fattinger, K., Funk, C., Pantze, M., Weber, C., Reichen, J., Stieger, B., Meier, P. J., The endothelin antagonist bosentan inhibits the canalicular bile salt export pump a potential mechanism for hepatic... 

Kato, Y., Akhteruzzaman, S., Hisaka, A., Sugiyama, Y., Hepatobiliary transport governs overall elimination of peptidic endothelin antagonists in rats,/. Pharmacol. Exp. Ther. 1999, 288, 568-574. 

In conclusion, the use of specific endothelin antagonists must be considered in the treatment of sickle cell disease as an alternative to HU, whose potential longterm mutagenic/carcinogenic effect is still under debate [36], especially in children. 

Sanders et al. [133] found that although quercetin treatment of streptozotocin diabetic rats diminished oxidized glutathione in brain and hepatic glutathione peroxidase activity, this flavonoid enhanced hepatic lipid peroxidation, decreased hepatic glutathione level, and increased renal and cardiac glutathione peroxidase activity. In authors opinion the partial prooxidant effect of quercetin questions the efficacy of quercetin therapy in diabetic patients. (Antioxidant and prooxidant activities of flavonoids are discussed in Chapter 29.) Administration of endothelin antagonist J-104132 to streptozotocin-induced diabetic rats inhibited the enhanced endothelin-1-stimulated superoxide production [134]. Interleukin-10 preserved endothelium-dependent vasorelaxation in streptozotocin-induced diabetic mice probably by reducing superoxide production by xanthine oxidase [135]. 

Fig. 3.6 Removal of H-bond donors as a synthetic strategy for a series of azole-containing endothelin antagonists aimed at improving bioavailability by lowering H-bonding potential [10].

A similar example, also from endothelin antagonists, is the replacement of the amide group (Figure 3.7) in a series of amidothiophenesulfonamides with acetyl [11]. This move retained in vitro potency, but markedly improved oral bioavailability. 

K. Oda, T. Yamamura, K. Hayakawa, Discovery of IRL 3461 A novel and potent endothelin antagonist with balanced ETa/ETb affinity, Bioorg. Med. Chem. Lett. 

Early work in the field has established the synthetic strategies and analytical tools for such class of libraries (for reviews see refs[111 112 456]). As listed in Table 13, the first generation of cyclic peptide libraries focused on biologically active sequences such as the cell adhesion RGD motif, the antileukemic heptapeptide stylostatin, or endothelin antagonists, but also on metal-binding sequence motifs and on the de novo discovery of bioactive cyclic peptides without sequence-biased motifs. Moreover, synthetic questions were addressed such as the sequence dependency of peptide cyclization reactions (see Table 13). 

The formation of endothelins can be blocked by inhibiting endothelin-converting enzyme with phosphoramidon. Phosphoramidon is not specific for endothelin-converting enzyme, but several more selective inhibitors are now available for research. Although the therapeutic potential of these drugs appeared similar to that of the endothelin receptor antagonists (see below), their use has been eclipsed by endothelin antagonists. 

PHYSIOLOGIC PATHOLOGIC ROLES OF ENDOTHELIN EFFECTS OF ENDOTHELIN ANTAGONISTS... 

In a double-blind, placebo-controlled study, the Bosentan Randomized trial of Endothelin Antagonist Therapy for Pulmonary Arterial I lypertension (BREATHE-2), 33 patients took epoprostenol (2 ng/kg/ min initially, increasing to a mean dosage of 14 ng/kg/min at week 16) and were then randomized for 16 weeks in a 2 1 ratio to bosentan (62.5 mg bd for 4 weeks then 125 mg bd) or placebo (11). There was a non-significant trend towards hemodynamic and clinical improvement with to the combination. There were several early and late major complications (four withdrawals with bosentan + epoprostenol two deaths due to cardiopulmonary failure, one clinical worsening, and one increase in hepatic transaminases and one withdrawal due to increased hepatic transaminases with placebo + epoprostenol. Power was the major limitation of this study, in which only 33 patients were enrolled, and the results should be interpreted with caution. Additional information is needed to evaluate the benefit to harm balance of combined bosentan + epoprostenol therapy in pulmonary arterial hypertension. 

Physiologic Pathologic Roles of Endothelin Effects of Endothelin Antagonists... 

There is increasing evidence that endothelins participate in a variety of cardiovascular diseases, including hypertension, cardiac hypertrophy, heart failure, atherosclerosis, coronary artery disease, and myocardial infarction. Endothelins have also been implicated in pulmonary diseases, including asthma and pulmonary hypertension, as well as in several renal diseases. This evidence includes findings of increased endothelin levels in the blood, increased expression of endothelin mRNA in endothelial or vascular smooth muscle cells, and the responses to administration of endothelin antagonists. 

Endothelin antagonists have considerable potential in the treatment of these diseases. In clinical trials, bosentan and other nonselective antagonists as well as ETA-selective antagonists have produced beneficial effects on hemodynamics and other symptoms in heart failure, pulmonary... 

Figure 2 Comparison between the uptake clearance obtained in vivo and that extrapolated from the in vitro transport study of endothelin antagonists. In vivo uptake clearance of endothelin antagonists (BQ-123, BQ-518, BQ-485, compound A) was evaluated by integration plot analysis using the plasma concentration-time profile after intravenous administration (500 nmol/kg) and the amount of drug in the liver and that excreted in the bile. In vitro hepatic uptake clearance was measured using isolated rat hepatocytes and was extrapolated to the in vivo uptake clearance assuming the well-stirred model. Source From Ref. 5.

Endothelin Antagonists for the Treatment of Pulmonary Arterial Hypertension... 

---