2. Academic Validation
  3. Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere

Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere

  • Chem Pharm Bull (Tokyo). 2000 Sep;48(9):1310-26. doi: 10.1248/cpb.48.1310.
T Mimoto 1,  N Hattori,  H Takaku,  S Kisanuki,  T Fukazawa,  K Terashima,  R Kato,  S Nojima,  S Misawa,  T Ueno,  J Imai,  H Enomoto,  S Tanaka,  H Sakikawa,  M Shintani,  H Hayashi,  Y Kiso
Affiliations

Affiliation

  • 1 Pharmaceuticals & Biotechnology Laboaratory, Japan Energy Corporation, Saitama.
PMID: 10993230 DOI: 10.1248/cpb.48.1310
Abstract

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).

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