Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere
| Autor: | Sumitsugu Kisanuki, Haruo Takaku, Hiroshi Enomoto, Naoko Hattori, Satoru Misawa, Hideya Hayashi, Hiroshi Sakikawa, Shigeki Tanaka, Yoshiaki Kiso, Keisuke Terashima, Ryohei Kato, Satoshi Nojima, Makoto Shintani, Tsutomu Mimoto, Tominaga Fukazawa, Junya Imai, Takamasa Ueno |
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| Rok vydání: | 2000 |
| Předmět: |
Male
Peptidomimetic Stereochemistry Isostere medicine.medical_treatment Tripeptide Antiviral Agents Rats Sprague-Dawley Structure-Activity Relationship Drug Discovery medicine HIV Protease Inhibitor Animals Protease inhibitor (pharmacology) chemistry.chemical_classification Protease biology Chemistry General Chemistry General Medicine HIV Protease Inhibitors Rats Enzyme Biochemistry Enzyme inhibitor Drug Design biology.protein Oligopeptides |
| Zdroj: | Chemicalpharmaceutical bulletin. 48(9) |
| ISSN: | 0009-2363 |
| Popis: | We designed and synthesized a new class of peptidomimetic human immunodeficiency virus protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl isostere as the active moiety. From a structure-activity relationship study of HIV-1 protease inhibition, enzyme selectivity for other aspartyl proteases, the antiviral activity and pharmacokinetics in rats, 24c (KNI-227) and 24d (KNI-272, our first clinical candidate) were found to be selective and orally potent HIV protease inhibitors. Moreover, an improvement of the pharmacokinetic features of KNI-272 provided two long-lasting and highly bioavailable compounds (24g: JE-2178, 24h: JE-2179). |
| Databáze: | OpenAIRE |
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