2. Academic Validation
  3. Small-sized human immunodeficiency virus type-1 protease inhibitors containing allophenylnorstatine to explore the S2' pocket

Small-sized human immunodeficiency virus type-1 protease inhibitors containing allophenylnorstatine to explore the S2' pocket

  • J Med Chem. 2009 Dec 10;52(23):7604-17. doi: 10.1021/jm9005115.
Koushi Hidaka 1,  Tooru Kimura,  Hamdy M Abdel-Rahman,  Jeffrey-Tri Nguyen,  Keith F McDaniel,  William E Kohlbrenner,  Akhteruzzaman Molla,  Motoyasu Adachi,  Taro Tamada,  Ryota Kuroki,  Noriko Katsuki,  Yoshiaki Tanaka,  Hikaru Matsumoto,  Jun Wang,  Yoshio Hayashi,  Dale J Kempf,  Yoshiaki Kiso
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
PMID: 19954246 DOI: 10.1021/jm9005115
Abstract

A series of HIV Protease Inhibitor based on the allophenylnorstatine structure with various P(2)' moieties were synthesized. Among these analogues, we discovered that a small allyl group would maintain potent Enzyme inhibitory activity compared to the o-methylbenzyl moiety in clinical candidate 1 (KNI-764, also known as JE-2147, AG-1776, or SM-319777). Introduction of an anilinic amino group to 2 (KNI-727) improved water-solubility and anti-HIV-1 activity. X-ray crystallographic analysis of 13k (KNI-1689) with a beta-methallyl group at P(2)' position revealed hydrophobic interactions with Ala28, Ile84, and Ile50' similar to that of 1. The presence of an additional methyl group on the allyl group in compound 13k significantly increased anti-HIV activity over 1 while providing a rational drug design for structural minimization and improving membrane permeability.

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