8 research outputs found
The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase
AbstractBackground: The p38 mitogen-activated protein (MAP) kinase regulates signal transduction in response to environmental stress. Pyridinylimidazole compounds are specific inhibitors of p38 MAP kinase that block the production of the cytokines interleukin-1 β and tumor necrosis factor α, and they are effective in animal models of arthritis, bone resorption and endotoxin shock. These compounds have been useful probes for studying the physiological functions of the p38-mediated MAP kinase pathway.Results: We report the crystal structure of a novel pyridinylimidazole compound complexed with p38 MAP kinase, and we demonstrate that this compound binds to the same site on the kinase as does ATP. Mutagenesis showed that a single residue difference between p38 MAP kinase and other MAP kinases is sufficient to confer selectivity among pyridinylimidazole compounds.Conclusions: Our results reveal how pyridinylimidazole compounds are potent and selective inhibitors of p38 MAP kinase but not other MAP kinases. It should now be possible to design other specific inhibitors of activated p38 MAP kinase using the structure of the nonphosphorylated enzyme
Synthesis of a Tetrahydronaphthyridine Spiropyrimidinetrione DNA Gyrase Inhibiting Antibacterial Agent - Differential Substitution at all Five Carbon Atoms of Pyridine.
The
synthesis of (−)-<b>1</b>, a potent antibacterial
agent, was achieved stereoselectively in nine steps from readily available
starting materials. Directed metalations were developed to assemble
a pentasubstituted pyridine with appropriately positioned aldehyde
and dimethylmorpholine substituents for a key tertiary amino effect
reaction (T-reaction) that led to the spirocylic architecture. Ultimately,
(−)-<b>1</b> was isolated as the thermodynamically most
favored stereoisomer
Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization
The
compounds described herein with a spirocyclic architecture
fused to a benzisoxazole ring represent a new class of antibacterial
agents that operate by inhibition of DNA gyrase as corroborated in
an enzyme assay and by the inhibition of precursor thymidine into
DNA during cell growth. Activity resided in the configurationally
lowest energy (2<i>S</i>,4<i>R</i>,4a<i>R</i>) diastereomer. Highly active compounds against Staphylococcus
aureus had sufficiently high solubility, high plasma
protein free fraction, and favorable pharmacokinetics to suggest that
in vivo efficacy could be demonstrated, which was realized with compound
(−)-<b>1</b> in S. aureus mouse infection models. A high drug exposure NOEL on oral dosing
in the rat suggested that a high therapeutic margin could be achieved.
Importantly, (−)-<b>1</b> was not cross-resistant with
other DNA gyrase inhibitors such as fluoroquinolone and aminocoumarin
antibacterials. Hence, this class shows considerable promise for the
treatment of infections caused by multidrug resistant bacteria, including S. aureus
Discovery of Novel DNA Gyrase Inhibiting Spiropyrimidinetriones: Benzisoxazole Fusion with N‑Linked Oxazolidinone Substituents Leading to a Clinical Candidate (ETX0914)
A novel class of bacterial type-II
topoisomerase inhibitor displaying
a spiropyrimidinetrione architecture fused to a benzisoxazole scaffold
shows potent activity against Gram-positive and fastidious Gram-negative
bacteria. Here, we describe a series of <i>N</i>-linked
oxazolidinone substituents on the benzisoxazole that improve upon
the antibacterial activity of initially described compounds of the
class, show favorable PK properties, and demonstrate efficacy in an
in vivo Staphylococcus aureus infection
model. Inhibition of the topoisomerases DNA gyrase and topoisomerase
IV from both Gram-positive and a Gram-negative organisms was demonstrated.
Compounds showed a clean in vitro toxicity profile, including no genotoxicity
and no bone marrow toxicity at the highest evaluated concentrations
or other issues that have been problematic for some fluoroquinolones.
Compound <b>1u</b> was identified for advancement into human
clinical trials for treatment of uncomplicated gonorrhea based on
a variety of beneficial attributes including the potent activity and
the favorable safety profile
Discovery of Efficacious Pseudomonas aeruginosa-Targeted Siderophore-Conjugated Monocarbams by Application of a Semi-Mechanistic PK/PD Model
In order to identify new agents for the treatment of Pseudomonas aeruginosa infections to address the serious threat to society posed by the evolution of multi-drug resistant P. aeruginosa, we focused on the well established family of Beta-lactams antibiotics. There is evidence they are effective against the target pathogen and their resistance profiles and pharmacology are well established. To address the major resistance mechanisms to other Beta-lactam antibiotics we studied siderophore-conjugated monocarbams. This class of monocyclic Beta-lactams is stable to metallo Beta-lactamases and they have excellent P. aeruginosa activities due to their ability to exploit the iron uptake machinery of the Gram-negative bacteria. Our medicinal chemistry plan focused on identifying a molecule with optimal potency and physical properties and activity for in vivo efficacy. We examined modifications to the monocarbam linker, the siderophore, and the oxime portion of the molecules. Through these efforts we identified a series of pyrrolidinone-based monocarbams which have good P. aeruginosa cellular activity (P. aeruginosa MIC90 = 2 g/ml), excellent free fraction levels (> 20 % free) and good hydrolytic stability (t1/2 ≥ 100 h). In order to differentiate our compounds and enable prioritization for future in vivo studies, we developed a robust mechanistic PK/PD model which enables prediction of in vivo efficacy from in vitro data
The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase
Discovery of Efficacious Pseudomonas aeruginosa-Targeted Siderophore-Conjugated Monocarbams by Application of a Semi-mechanistic Pharmacokinetic/Pharmacodynamic Model
To identify new agents
for the treatment of multi-drug-resistant Pseudomonas
aeruginosa, we focused on siderophore-conjugated
monocarbams. This class of monocyclic β-lactams are stable to
metallo-β-lactamases and have excellent P. aeruginosa activities due to their ability to exploit the iron uptake machinery
of Gram-negative bacteria. Our medicinal chemistry plan focused on
identifying a molecule with optimal potency and physical properties
and activity for in vivo efficacy. Modifications to the monocarbam
linker, siderophore, and oxime portion of the molecules were examined.
Through these efforts, a series of pyrrolidinone-based monocarbams
with good P. aeruginosa cellular activity
(P. aeruginosa MIC<sub>90</sub> = 2
μg/mL), free fraction levels (>20% free), and hydrolytic
stability
(<i>t</i><sub>1/2</sub> ≥ 100 h) were identified.
To differentiate the lead compounds and enable prioritization for
in vivo studies, we applied a semi-mechanistic pharmacokinetic/pharmacodynamic
model to enable prediction of in vivo efficacy from in vitro data