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 solubility profiles. Poor solubility characteristics displayed by 1 required a complex buffered formulation in order to conduct iv studies. To overcome th...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1999-06, Vol.42 (12), p.2162-2168
Main Authors: Patt, William C, Cheng, Xue-Min, Repine, Joseph T, Lee, Chet, Reisdorph, Bill R, Massa, Mark A, Doherty, Annette M, Welch, Kathleen M, Bryant, John W, Flynn, Michael A, Walker, Donnelle M, Schroeder, Richard L, Haleen, Stephen J, Keiser, Joan A
Format: Article
Language:English
Subjects:
Animals
Antihypertensive agents
Benzenesulfonates - chemical synthesis
Benzenesulfonates - chemistry
Benzenesulfonates - pharmacology
Biological and medical sciences
Cardiovascular system
Dioxoles - chemical synthesis
Dioxoles - chemistry
Dioxoles - pharmacology
Endothelin Receptor Antagonists
Femoral Artery - drug effects
Femoral Artery - physiology
Hydrogen-Ion Concentration
Hypertension, Pulmonary - etiology
Hypertension, Pulmonary - prevention & control
Hypoxia - complications
In Vitro Techniques
Medical sciences
Muscle Contraction - drug effects
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - physiology
Pharmacology. Drug treatments
Rabbits
Rats
Rats, Sprague-Dawley
Receptor, Endothelin A
Solubility
Structure-Activity Relationship
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Description
Summary:Continued development around our ETA-selective endothelin (ET) antagonist 1 (CI-1020) has led to the synthesis of analogues with improved aqueous solubility profiles. Poor solubility characteristics displayed by 1 required a complex buffered formulation in order to conduct iv studies. To overcome the use of specific iv formulations for preclinical studies on additional drug candidates, analogues with improved aqueous solubility were desired. Several 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 retained equivalent or improved ETA receptor selectivity and antagonist potency, versus 1, both in vitro and in vivo. Compound 29, which contains as a substituent 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 superior aqueous solubility and solubility duration, compared to 1. Furthermore, 29 after iv infusion displays improved activity to 1 in preventing acute hypoxia-induced pulmonary hypertension in rats with an ED50 = 0.3 μg/kg/h.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm980504w