Small-sized human immunodeficiency virus type-1 protease inhibitors containing allophenylnorstatine to explore the S2' pocket.
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.
Hidaka
Koushi
K
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Kimura
Tooru
T
Abdel-Rahman
Hamdy M
HM
Nguyen
Jeffrey-Tri
JT
McDaniel
Keith F
KF
Kohlbrenner
William E
WE
Molla
Akhteruzzaman
A
Adachi
Motoyasu
M
Tamada
Taro
T
Kuroki
Ryota
R
Katsuki
Noriko
N
Tanaka
Yoshiaki
Y
Matsumoto
Hikaru
H
Wang
Jun
J
Hayashi
Yoshio
Y
Kempf
Dale J
DJ
Kiso
Yoshiaki
Y
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
D017320:HIV Protease Inhibitors; D010654:Phenylbutyrates; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1