Potent and Selective Non-Peptidic Inhibitors of Endothelin-Converting Enzyme-1 with Sustained Duration of Action
| Autor: | John Moliterni, Arco Y. Jeng, John Fitt, Lisa B. Stamford, Eli M. Wallace, L. Blanchard, Mary Chou, S. De Lombaert, Jenny Tan, Paula Savage, Daniel Hoyer, N. Marcopoulos, D. Simonsbergen, Angelo J. Trapani, Yoshitaka Satoh |
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| Rok vydání: | 2000 |
| Předmět: |
Male
medicine.hormone Endothelin converting enzyme 1 Stereochemistry Organophosphonates Tetrazoles Blood Pressure Endothelin-Converting Enzymes Rats Sprague-Dawley Endothelins Structure-Activity Relationship chemistry.chemical_compound In vivo Drug Discovery medicine Animals Aspartic Acid Endopeptidases Humans Structure–activity relationship Tetrazole Enzyme Inhibitors Protein Precursors education Benzofurans education.field_of_study Endothelin-1 biology Phosphoramidon Metalloendopeptidases Stereoisomerism Endothelin 1 Combinatorial chemistry Rats chemistry Enzyme inhibitor biology.protein Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 43:488-504 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm990507o |
| Popis: | Potent and selective non-peptidic inhibitors of human endothelin-converting enzyme-1 (ECE-1) have been designed as potential modulators of endothelin (ET-1) production in vivo. Because of its unique structural characteristics and long duration of action in vivo, the dual ECE-1 and neutral endopeptidase 24.11 (NEP) inhibitor, CGS 26303, was selected as an attractive lead for further optimization of potency and selectivity. Replacement of the P(1)' biphenyl substituent of CGS 26303 by a conformationally restricted 3-dibenzofuranyl group led to more potent and more selective ECE-1 inhibitors, such as the tetrazole 27. The remarkable effect of this P(1)' modification allowed for the first time phosphonomethylcarboxylic acids, such as 29, to display both potent (IC(50) = 22 nM) and selective (104-fold vs NEP) ECE-1 inhibition. Chemoenzymatic syntheses of the new alpha-amino acid (S)-3-dibenzofuran-3-ylalanine intermediate were developed, and improved procedures to generate substituted alpha-aminoalkylphosphonic acids were devised to support the production of various analogues. Although additional gains in intrinsic ECE-1 inhibitory potency could occasionally be achieved by addition of a P(1) side chain, these compounds (e.g. 43a) showed poor functional activity in vivo in the big ET-1 pressor test. Phosphonoalkyl dipeptides featuring 3-dibenzofuranyl groups in both the P(1)' and P(2)' positions were also very potent ECE-1 inhibitors, albeit lacking the desired selectivity against NEP. Functionally, 27and 29 were the two most efficacious compounds from this study, producing sustained inhibition of ECE-1 activity in rats, as measured by their ability to block the hypertensive effects induced by big ET-1. This profile was similar to that of a potent ET(A)/ET(B) dual receptor antagonist, SB 209670. Due to their favorable in vitro and in vivo profiles, 27 (CGS 34043) and 29 (CGS 35066) constitute new pharmacological tools useful in assessing the role of ECE-1 in pathological conditions. |
| Databáze: | OpenAIRE |
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