Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety

Abstract 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.