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Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety
Author(s) -
Cohen Frederick,
Aggen James B.,
Andrews Logan D.,
Assar Zahra,
Boggs Jen,
Choi Taylor,
Dozzo Paola,
Easterday Ashton N.,
Haglund Cat M.,
Hildebrandt Darin J.,
Holt Melissa C.,
Joly Kristin,
Jubb Adrian,
Kamal Zeeshan,
Kane Timothy R.,
Konradi Andrei W.,
Krause Kevin M.,
Linsell Martin S.,
Machajewski Timothy D.,
Miroshnikova Olga,
Moser Heinz E.,
Nieto Vincent,
Phan Thu,
Plato Craig,
Serio Alisa W.,
Seroogy Julie,
Shakhmin Anton,
Stein Adam J.,
Sun Alex D.,
Sviridov Serguei,
Wang Zhan,
Wlasichuk Kenneth,
Yang Wen,
Zhou Xiaoming,
Zhu Hai,
Cirz Ryan T.
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900287
Subject(s) - prodrug , benzamide , pharmacology , chemistry , pharmacokinetics , potency , safety pharmacology , drug , medicine , biochemistry , stereochemistry , in vitro
UDP‐3‐ O ‐( R ‐3‐hydroxymyristoyl)‐ N ‐acetylglucosamine deacetylase (LpxC) is a Zn 2+ 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‐(((1 R ,2 R )‐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.