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
Sirtuin 2 (SIRT2) is one of the sirtuins, a family of NAD(+)-dependent deacetylases that act on a variety of histone and non-histone substrates. Accumulating biological functions and potential therapeutic applications have drawn interest in the discovery and development of SIRT2 inhibitors. Herein we report our discovery of novel SIRT2 inhibitors using a fragment-based approach. Inspired by the purported close binding proximity of suramin and nicotinamide, we prepared two sets of fragments, namely, the naphthylamide sulfonic acids and the naphthalene-benzamides and -nicotinamides. Biochemical evaluation of these two series provided structure-activity relationship (SAR) information, which led to the design of (5-benzamidonaphthalen-1/2-yloxy)nicotinamide derivatives. Among these inhibitors, one compound exhibited high anti-SIRT2 activity (48 nM) and excellent selectivity for SIRT2 over SIRT1 and SIRT3. In vitro, it also increased the acetylation level of α-tubulin, a well-established SIRT2 substrate, in both concentration- and time-dependent manners. Further kinetic studies revealed that this compound behaves as a competitive inhibitor against the peptide substrate and most likely as a noncompetitive inhibitor against NAD(+). Taken together, these results indicate that we have discovered a potent and selective SIRT2 inhibitor whose novel structure merits further exploration.
Subject(s)
Enzyme Inhibitors/pharmacology , Sirtuin 2/antagonists & inhibitors , Animals , Dogs , Drug Design , Drug Discovery , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/chemistry , Humans , Ligands , MCF-7 Cells/drug effects , Madin Darby Canine Kidney Cells , Molecular Structure , Niacinamide/chemistry , Structure-Activity Relationship , Sulfonic Acids/chemistry , Suramin/chemistry , Suramin/pharmacologyABSTRACT
Photoinitiated [6pi + 2pi] cycloadditions of allenes with (eta(6)-cycloheptatriene)tricarbonylchromium(0) (1) are described. An example of asymmetric induction obtained by reaction of 1 with a chiral 1,3-disubstituted allene is also reported.
