Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety

被引：59

作者：

Cohen, Frederick ^{[1
]}

Aggen, James B. ^{[1
]}

Andrews, Logan D. ^{[1
]}

Assar, Zahra ^{[2
]}

Boggs, Jen ^{[1
]}

Choi, Taylor ^{[1
]}

Dozzo, Paola ^{[1
]}

Easterday, Ashton N. ^{[1
]}

Haglund, Cat M. ^{[1
]}

Hildebrandt, Darin J. ^{[1
]}

Holt, Melissa C. ^{[2
]}

Joly, Kristin ^{[3
]}

Jubb, Adrian ^{[1
]}

Kamal, Zeeshan ^{[4
]}

Kane, Timothy R. ^{[1
]}

Konradi, Andrei W. ^{[5
]}

Krause, Kevin M. ^{[1
]}

Linsell, Martin S. ^{[1
]}

Machajewski, Timothy D. ^{[1
]}

Miroshnikova, Olga ^{[4
]}

Moser, Heinz E. ^{[1
]}

Nieto, Vincent ^{[1
]}

Thu Phan ^{[4
]}

Plato, Craig ^{[3
]}

Serio, Alisa W. ^{[1
]}

Seroogy, Julie ^{[1
]}

Shakhmin, Anton ^{[4
]}

Stein, Adam J. ^{[2
]}

Sun, Alex D. ^{[4
]}

Sviridov, Serguei ^{[4
]}

Wang, Zhan ^{[4
]}

Wlasichuk, Kenneth ^{[1
]}

Yang, Wen ^{[4
]}

Zhou, Xiaoming ^{[6
]}

Zhu, Hai ^{[4
]}

Cirz, Ryan T. ^{[1
]}

机构：

[1] Achaogen Inc, 1 Tower Pl,Suite 400, San Francisco, CA 94080 USA

[2] Cayman Chem Co, 1180 East Ellsworth, Ann Arbor, MI 48108 USA

[3] Plato BioPharma Inc, Unit 300, 7581 West 103rd Ave, Westminster, CO 80021 USA

[4] Nanosyn Inc, 3100 Cent Expressway, Santa Clara, CA 95051 USA

[5] Konradi Mol, 30 Victoria Rd, Burlingame, CA 94010 USA

[6] Pharmaron Inc, BDA, 6 Tai He Rd, Beijing 100176, Peoples R China

来源：

CHEMMEDCHEM | 2019年 / 14卷 / 16期

基金：

美国国家卫生研究院;

关键词：

amines; antibiotics; inhibitors; LpxC; prodrugs; Pseudomonas; zwitterions; DRUGS;

D O I：

10.1002/cmdc.201900287

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL(-1) for parenteral administration and conversion into the active drug with a t(1/2) of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.

引用

页码：1560 / 1572

页数：13

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