Novel orally active inhibitors of β-1,3-glucan synthesis derived from enfumafungin

被引：20

作者：

Apgar, James M. ^{[1
]}

Wilkening, Robert R. ^{[1
]}

Greenlee, Mark L. ^{[1
]}

Balkovec, James M. ^{[1
]}

Flattery, Amy M. ^{[1
]}

Abruzzo, George K. ^{[1
]}

Galgoci, Andrew M. ^{[1
]}

Giacobbe, Robert A. ^{[1
]}

Gill, Charles J. ^{[1
]}

Hsu, Ming Jo ^{[1
]}

Liberator, Paul ^{[1
]}

Misura, Andrew S. ^{[1
]}

Motyl, Mary ^{[1
]}

Kahn, Jennifer Nielsen ^{[1
]}

Powles, Maryann ^{[1
]}

Racine, Fred ^{[1
]}

Dragovic, Jasminka ^{[1
]}

Habulihaz, Bahanu ^{[1
]}

Fan, Weiming ^{[2
]}

Kirwan, Robin ^{[2
]}

Lee, Shu ^{[2
]}

Liu, Hao ^{[2
]}

Mamai, Ahmed ^{[2
]}

Nelson, Kingsley ^{[2
]}

Peel, Michael ^{[2
]}

机构：

[1] Merck & Co Inc, Merck Res Labs, Kenilworth, NJ 07033 USA

[2] Scynexis Inc, Res Triangle Pk, NC 27709 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 24期

关键词：

beta-1,3-Glucan synthesis inhibitor; Enfumafungin; Antifungal; Candidiasis; Oral bioavailability; GLUCAN SYNTHASE INHIBITORS; DRUG-RESISTANCE MECHANISMS; INVASIVE CANDIDIASIS; PYRIDAZINONE SERIES; DISCOVERY; EPIDEMIOLOGY; OPTIMIZATION; PERSPECTIVES; DERIVATIVES; ANTIFUNGALS;

D O I：

10.1016/j.bmcl.2015.10.011

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The clinical success of the echinocandins, which can only be administered parentally, has validated beta-1, 3-glucan synthase (GS) as an antifungal target. Semi-synthetic modification of enfumafungin, a triterpene glycoside natural product, was performed with the aim of producing a new class of orally active GS inhibitors. Replacement of the C2 acetoxy moiety with various heterocycles did not improve GS or antifungal potency. However, replacement of the C3 glycoside with an aminoether moiety dramatically improved oral pharmacokinetic (PK) properties while maintaining GS and antifungal potency. Installing an aminotetrazole at C2 in conjunction with an N-alkylated aminoether at C3 produced derivatives with significantly improved GS and antifungal potency that exhibited robust oral efficacy in a murine model of disseminated candidiasis. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：5813 / 5818

页数：6

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