Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety

被引：60

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

共 26 条

[1]

[Anonymous], 2007, PRODRUGS BIOTECHNOLO, DOI DOI 10.1007/978-0-387-49785-3_16

[2]

[Anonymous], 2015, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically: M07-A10

[3]

Approved Standard

[4]

[Anonymous], 2013, Antibiotic resistance threats in the United States, 2013

[5] Re-estimating annual deaths due to multidrug-resistant organism infections [J].

Burnham, Jason P. ;

Olsen, Margaret A. ;

Kollef, Marin H. .

INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY, 2019, 40 (01) :112-113

[6] Pan-Resistant New Delhi Metallo-Beta-Lactamase-Producing Klebsiella pneumoniae - Washoe County, Nevada, 2016 [J].

Chen, Lei ;

Todd, Randall ;

Kiehlbauch, Julia ;

Walters, Maroya ;

Kallen, Alexander .

MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT, 2017, 66 (01) :33-33

[7]

Cohen F., 2017, Int. PCT Pub., Patent No. [WO2017223349, 2017223349]

[8] THE IMPORTANCE OF THE GEOMETRIC MEAN MIC [J].

DAVIES, BI .

JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 1990, 25 (03) :471-472

[9] Antibacterial Drug Discovery Targeting the Lipopolysaccharide Biosynthetic Enzyme LpxC [J].

Erwin, Alice L. .

COLD SPRING HARBOR PERSPECTIVES IN MEDICINE, 2016, 6 (07)

[10] Exploring the UDP pocket of LpxC through amino acid analogs [J].

Hale, Michael R. ;

Hill, Pamela ;

Lahiri, Sushmita ;

Miller, Matthew D. ;

Ross, Philip ;

Alm, Richard ;

Gao, Ning ;

Kutschke, Amy ;

Johnstone, Michele ;

Prince, Bryan ;

Thresher, Jason ;

Yang, Wei .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (08) :2362-2367

← 1 2 3 →