title: Small-sized human immunodeficiency virus type-1 protease inhibitors containing allophenylnorstatine to explore the S2' pocket.
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.
authors: Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors: Koushi
authors: K
authors: Hidaka
authors: Tooru
authors: T
authors: Kimura
authors: Hamdy M
authors: HM
authors: Abdel-Rahman
authors: Jeffrey-Tri
authors: JT
authors: Nguyen
authors: Keith F
authors: KF
authors: McDaniel
authors: William E
authors: WE
authors: Kohlbrenner
authors: Akhteruzzaman
authors: A
authors: Molla
authors: Motoyasu
authors: M
authors: Adachi
authors: Taro
authors: T
authors: Tamada
authors: Ryota
authors: R
authors: Kuroki
authors: Noriko
authors: N
authors: Katsuki
authors: Yoshiaki
authors: Y
authors: Tanaka
authors: Hikaru
authors: H
authors: Matsumoto
authors: Jun
authors: J
authors: Wang
authors: Yoshio
authors: Y
authors: Hayashi
authors: Dale J
authors: DJ
authors: Kempf
authors: Yoshiaki
authors: Y
authors: Kiso
mesh_terms: D002460:Cell Line; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010654:Phenylbutyrates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D017320:HIV Protease Inhibitors; D010654:Phenylbutyrates; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1