ABSTRACT
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 >30â mg mL-1 for parenteral administration and conversion into the active drug with a t1/2 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.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Diynes/pharmacology , Enzyme Inhibitors/pharmacology , Heart/drug effects , Hydroxamic Acids/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/toxicity , Bacterial Proteins/antagonists & inhibitors , Cardiotoxicity , Diynes/chemical synthesis , Diynes/pharmacokinetics , Diynes/toxicity , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/toxicity , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacokinetics , Hydroxamic Acids/toxicity , Male , Molecular Structure , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Prodrugs/toxicity , Pseudomonas aeruginosa/drug effects , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
We report herein a general catalytic method for Csp(2)-Csp(3) bond formation through C-F activation. The process uses an inexpensive nickel complex with either diorganozinc or alkylzinc halide reagents, including those with ß-hydrogen atoms. A variety of fluorine substitution patterns and functional groups can be readily incorporated. Sequential reactions involving different precatalysts and coupling partners permit the synthesis of densely functionalized fluorinated building blocks.
Subject(s)
Coordination Complexes/chemistry , Fluorine/chemistry , Halogens/chemistry , Nickel/chemistry , Catalysis , Molecular StructureABSTRACT
A Ni-catalyzed, chemoselective cross-coupling reaction of polyfluoroarenes under mild reaction conditions is reported. A variety of fluorine-containing biaryls are synthesized in good-to-excellent yields. A wide range of substitution patterns and functional groups are tolerated.
Subject(s)
Hydrocarbons, Fluorinated/chemical synthesis , Nickel/chemistry , Catalysis , Combinatorial Chemistry Techniques , Hydrocarbons, Fluorinated/chemistry , Molecular StructureABSTRACT
This Perspective provides an overview of transition metal-catalyzed cross coupling reactions of polyfluoroarenes. When appropriate, stoichiometric C-F activation and subsequent reaction are briefly covered.
