Cayman scientists perform crystallization experiments, structure solutions, and final refinement of lead inhibitors of an enzyme involved in Gram(–) bacteria pathogenicity.

Frederick Cohen, James B. Aggen, Logan D. Andrews, Zahra Assar, Jen Boggs, Taylor Choi, Paola Dozzo, Ashton N. Easterday, Cat M. Haglund, Darin J. Hildebrandt, Melissa C. Holt, Kristin Joly, Adrian Jubb, Zeeshan Kamal, Timothy R. Kane, Andrei W. Konradi, Kevin M. Krause, Martin S. Linsell, Timothy D. Machajewski, Olga Miroshnikova, Heinz E. Moser, Vincent Nieto, Thu Phan, Craig Plato, Alisa W. Serio, Julie Seroogy, Anton Shakhmin, Adam J. Stein, Alex D. Sun, Serguei Sviridov, Zhan Wang, Kenneth Wlasichuk, Wen Yang, Xiaoming Zhou, Hai Zhu, Ryan T. Cirz

Highlights

• In an effort to develop new antibiotic therapies, candidate LpxC inhibitors were optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety.
• Crystal structures determined the key interactions of the inhibitors in the P. aeruginosa LpxC binding pocket, which led to the development of a prodrug with high solubility and rapid conversion to active drug upon i.v. administration.

Abstract

LpxC is a Zn²⁺ deacetylase that is essential for the survival of most pathogenic Gram(–) 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. We report here the effort beyond ACHN‐975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on overall profile, 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 solubility of >30 mg/mL for parenteral administration and conversion to the active drug with a T_1/2 of approximately 2 minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.

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