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Butenolide endothelin antagonists with improved aqueous solubility.
W C Patt1, X M Cheng, J T Repine
1Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
Journal of Medicinal Chemistry
|June 23, 1999
Summary
Researchers developed new endothelin (ET) antagonists with better solubility. These compounds maintain strong ETA receptor selectivity and potency, offering improved options for preclinical studies and treating pulmonary hypertension.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Cardiovascular Research
Background:
- Endothelin (ET) antagonist 1 (CI-1020) demonstrated ETA-selective properties but suffered from poor aqueous solubility.
- The limited solubility of CI-1020 necessitated complex intravenous (IV) buffered formulations for preclinical investigations.
- Improved aqueous solubility was crucial for developing new drug candidates without specialized IV formulations.
Purpose of the Study:
- To synthesize and characterize novel ETA-selective endothelin antagonist analogues with enhanced aqueous solubility.
- To evaluate the in vitro and in vivo efficacy, selectivity, and potency of these new analogues compared to the parent compound.
- To identify a lead compound suitable for further preclinical development, overcoming the formulation challenges of CI-1020.
Main Methods:
- Synthesis of endothelin antagonist analogues incorporating acid or base addition salt-forming substituents.
- Assessment of aqueous solubility and solubility duration for the synthesized analogues.
- In vitro evaluation of ETA receptor selectivity and antagonist potency (IC50, KB).
- In vivo assessment of efficacy in a rat model of acute hypoxia-induced pulmonary hypertension.
Main Results:
- Several analogues exhibited significantly improved aqueous solubility and solubility duration compared to CI-1020.
- These analogues retained or demonstrated superior ETA receptor selectivity and antagonist potency.
- Compound 29, a sulfonic acid sodium salt derivative, showed an ETA IC50 of 0.38 nM and 4200-fold ETA selectivity.
- Compound 29 demonstrated superior efficacy in preventing hypoxia-induced pulmonary hypertension in rats (ED50 = 0.3 microg/kg/h).
Conclusions:
- Novel ETA-selective endothelin antagonists with substantially improved aqueous solubility have been successfully developed.
- These analogues maintain or enhance the pharmacological profile of the parent compound, offering advantages for formulation and preclinical studies.
- Compound 29 represents a promising candidate for further development due to its balanced efficacy, selectivity, and improved solubility characteristics.