An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus

被引：36
作者：
Feil, Susanne C. [1 ]
Hamilton, Stephanie
Krippner, Guy Y.
Lin, Bo
Luttick, Angela
McConnell, Darryl B.
Nearn, Roland
Parker, Michael W. [1 ,2 ]
Ryan, Jane
Stanislawski, Pauline C.
Tucker, Simon P.
Watson, Keith G.
Morton, Craig J. [1 ]
机构：
[1] St Vincents Inst, Biota Struct Biol Lab, Fitzroy, Vic 3065, Australia
[2] Univ Melbourne, Dept Biochem & Mol Biol, Mol Sci & Biotechnol Inst Bio21, Parkville, Vic 3010, Australia
来源：
ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 04期
关键词：
antiviral; rhinovirus; capsid; inhibitor; VITRO ANTIVIRAL ACTIVITY; HEALTHY-VOLUNTEERS; DOUBLE-BLIND; 3C PROTEASE; PIRODAVIR; COLDS; PLECONARIL; SAFETY; PHARMACOKINETICS; RUPRINTRIVIR;
D O I：
10.1021/ml2002955
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Respiratory infections caused by human rhinovirus are responsible for severe exacerbations of underlying clinical conditions such as asthma in addition to their economic cost in terms of lost working days due to illness. While several antiviral compounds for treating rhinoviral infections have been discovered, none have succeeded, to date, in reaching approval for clinical use. We have developed a potent, orally available rhinovirus inhibitor 6 that has progressed through early clinical trials. The compound shows favorable pharmacokinetic and activity profiles and has a confirmed mechanism of action through crystallographic studies of a rhinovirus compound complex. The compound has now progressed to phase IIb clinical studies of its effect on natural rhinovirus infection in humans.
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收藏
页码：303 / 307
页数：5
相关论文
共 25 条
[1]   MANY RHINOVIRUS SEROTYPES SHARE THE SAME CELLULAR RECEPTOR [J].
ABRAHAM, G ;
COLONNO, RJ .
JOURNAL OF VIROLOGY, 1984, 51 (02) :340-345
[2]   INVITRO ACTIVITY OF PIRODAVIR (R-77975), A SUBSTITUTED PHENOXY-PYRIDAZINAMINE WITH BROAD-SPECTRUM ANTIPICORNAVIRAL ACTIVITY [J].
ANDRIES, K ;
DEWINDT, B ;
SNOEKS, J ;
WILLEBRORDS, R ;
VANEEMEREN, K ;
STOKBROEKX, R ;
JANSSEN, PAJ .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1992, 36 (01) :100-107
[3]   2 GROUPS OF RHINOVIRUSES REVEALED BY A PANEL OF ANTIVIRAL COMPOUNDS PRESENT SEQUENCE DIVERGENCE AND DIFFERENTIAL PATHOGENICITY [J].
ANDRIES, K ;
DEWINDT, B ;
SNOEKS, J ;
WOUTERS, L ;
MOEREELS, H ;
LEWI, PJ ;
JANSSEN, PAJ .
JOURNAL OF VIROLOGY, 1990, 64 (03) :1117-1123
[4]  
Andries Koen, 1993, P179
[5]   Diagnosis and treatment of rhinovirus respiratory infections [J].
Anzueto, A ;
Niederman, MS .
CHEST, 2003, 123 (05) :1664-1672
[6]   In vitro activity of expanded-spectrum pyridazinyl oxime ethers related to pirodavir: Novel capsid-binding inhibitors with potent antipicornavirus activity [J].
Barnard, DL ;
Hubbard, VD ;
Smee, DF ;
Sidwell, RW ;
Watson, KGW ;
Tucker, SPT ;
Reece, PAR .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2004, 48 (05) :1766-1772
[7]   2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder [J].
Brown, RN ;
Cameron, R ;
Chalmers, DK ;
Hamilton, S ;
Luttick, A ;
Krippner, GY ;
McConnell, DB ;
Nearn, R ;
Stanislawski, PC ;
Tucker, SP ;
Watson, KG .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (08) :2051-2055
[8]   Selective Inhibitors of Picornavirus Replication [J].
De Palma, Armando M. ;
Vliegen, Inge ;
De Clercq, Erik ;
Neyts, Johan .
MEDICINAL RESEARCH REVIEWS, 2008, 28 (06) :823-884
[9]   The ABCs of Rhinoviruses, Wheezing, and Asthma [J].
Gern, James E. .
JOURNAL OF VIROLOGY, 2010, 84 (15) :7418-7426
[10]   Phase II, randomized, double-blind, placebo-controlled studies of ruprintrivir nasal spray 2-percent suspension for prevention and treatment of experimentally induced rhinovirus colds in healthy volunteers [J].
Hayden, FG ;
Turner, RB ;
Gwaltney, JM ;
Chi-Burris, K ;
Gersten, M ;
Hsyu, P ;
Patick, AK ;
Smith, GJ ;
Zalman, LS .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2003, 47 (12) :3907-3916
123