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

  title={Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere.},
  author={Tsutomu Mimoto and Naoko Hattori and Haruo Takaku and Sumitsugu Kisanuki and Tominaga Fukazawa and Keisuke Terashima and Ryohei Kato and Satoshi Nojima and Satoru Misawa and Takamasa Ueno and Junya Imai and Hiroshi Enomoto and S. Tanaka and Hiroshi Sakikawa and Makoto Shintani and Hideya Hayashi and Yoshiaki Kiso},
  journal={Chemical \& pharmaceutical bulletin},
  volume={48 9},
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… 
Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV.
Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-hIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain.
Identification of Highly Potent Human Immunodeficiency Virus Type-1 Protease Inhibitors against Lopinavir and Darunavir Resistant Viruses from Allophenylnorstatine-Based Peptidomimetics with P2 Tetrahydrofuranylglycine.
The results suggest that the strategy to design allophenylnorstatine-based peptidomimetics combined with Thfg residue would be promising for generating candidates to overcome multidrug resistance.
Rigid backbone moiety of KNI-272, a highly selective HIV protease inhibitor: methanol, acetone and dimethylsulfoxide solvated forms of 3-[3-benzyl-2-hydroxy-9-(isoquinolin-5-yloxy)-6-methylsulfanylmethyl-5,8-dioxo-4,7-diazanonanoyl]-N-tert-butyl-1,3-thiazolidine-4-carboxamide.
When crystals of kynostatin (KNI)-272, a highly selective HIV protease inhibitor containing allophenylnorstatine, were grown in three different solvent systems, the local conformations around the hydroxymethylcarbonyl (HMC) moiety, which mimics the structure of the transition state, were similar in all three forms.