Butenolide endothelin antagonists with improved aqueous solubility

Continued development around our ETA-selective endothelin (ET) antagonist 1 (CI-1020) has led to the synthesis of analogues with improved aqueous solu bility profiles. Poor solubility characteristics displayed by 1 required a complex buffered formulation in order to conduct iv studies. To overcome th e use of specific iv formulations for preclinical studies on additional dru g candidates, analogues with improved aqueous solubility were desired. Seve ral analogues were synthesized with substitution patterns that allowed for the formation of either acid or base addition salts. These derivatives had dramatically improved aqueous solubility. In addition, these analogues reta ined equivalent or improved ETA receptor selectivity and antagonist potency , versus 1, both in vitro and in vivo. Compound 29, which contains as a sub stituent the sodium salt of a sulfonic acid, has an ETA IC50 = 0.38 nM, ETA selectivity of 4200-fold, and ETA functional activity of K-B = 7.8, all of which are similar or superior to those of 1. Compound 29 also has vastly s uperior aqueous solubility and solubility duration, compared to 1. Furtherm ore, 29 after iv infusion displays improved activity to 1 in preventing acu te hypoxia-induced pulmonary hypertension in rats with an ED50 = 0.3 mu g/k g/h.