Design and synthesis of an orally active macrocyclic neutral endopeptidase 24.11 inhibitor
| Autor: | Jane Peppard, Angelo J. Trapani, Frank H Clarke, Macpherson Lawrence J, Erol K. Bayburt, Yumi Sakane, Michael Paul Capparelli, Carol Berry, R. D. Ghai, Regine Bohacek |
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| Rok vydání: | 1993 |
| Předmět: |
Models
Molecular Stereochemistry Molecular Sequence Data Thermolysin Administration Oral Biological Availability Crystallography X-Ray Peptides Cyclic chemistry.chemical_compound Drug Discovery Animals Computer Simulation Amino Acid Sequence Neprilysin Antihypertensive Agents chemistry.chemical_classification Binding Sites Dipeptide Molecular Structure biology Chemistry Active site Biological activity Rats Amino acid Hydroxyproline Enzyme inhibitor Drug Design Hypertension Lactam biology.protein Molecular Medicine Atrial Natriuretic Factor |
| Zdroj: | Journal of Medicinal Chemistry. 36:3821-3828 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00076a009 |
| Popis: | A potent macrocyclic inhibitor of neutral endopeptidase (NEP) 24.11 was designed using a computer model of the active site of thermolysin. This 10-membered ring lactam represents a general mimic for any hydrophobic dipeptide in which the two amino acid side chains bind to an enzyme in a contiguous orientation. The parent 10-membered ring lactam was synthesized and exhibited excellent potency as an NEP 24.11 inhibitor (IC50 = 3 nM). In order to improve oral bioavailability, various functionality was attached to the macrocycle. These modifications lead to CGS 25155, an orally active NEP 24.11 inhibitor that slows down the degradation of the cardiac hormone atrial natriuretic factor, producing a lowering of blood pressure in the DOCA-salt rat model of hypertension. |
| Databáze: | OpenAIRE |
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