ABSTRACT
Avibactam is a diazabicyclooctane ß-lactamase inhibitor possessing outstanding but incomplete efficacy against multidrug-resistant Gram-negative pathogens in combination with ß-lactam antibiotics. Significant pharmaceutical investment in generating derivatives of avibactam warrants a thorough characterization of their activity. We show here through structural and kinetic analysis that select diazabicyclooctane derivatives display effective but varied inhibition of two clinically important ß-lactamases (CTX-M-15 and OXA-48). Furthermore, these derivatives exhibit considerable antimicrobial activity (MIC ≤ 2 µg/mL) against clinical isolates of Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp. Imaging of cell phenotype along with structural and biochemical experiments unambiguously demonstrate that this activity, in E. coli, is a result of targeting penicillin-binding protein 2. Our results suggest that structure-activity relationship studies for the purpose of drug discovery must consider both ß-lactamases and penicillin-binding proteins as targets. We believe that this approach will yield next-generation combination or monotherapies with an expanded spectrum of activity against currently untreatable Gram-negative pathogens.
Subject(s)
Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacology , Penicillin-Binding Proteins/metabolism , beta-Lactamase Inhibitors/chemistry , beta-Lactamase Inhibitors/pharmacology , Kinetics , Microbial Sensitivity Tests , Protein ConformationABSTRACT
A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFß receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFß induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.
Subject(s)
Cicatrix/prevention & control , Drug Discovery , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Skin/drug effects , Animals , Models, Molecular , Phosphorylation , Rats , Receptor, Transforming Growth Factor-beta Type IABSTRACT
Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT(1A) partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT(1A) partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.
Subject(s)
Adrenergic Uptake Inhibitors/chemical synthesis , Drug Design , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Pyridines/chemical synthesis , Serotonin 5-HT1 Receptor Agonists , Serotonin Receptor Agonists/chemical synthesis , Adrenergic Uptake Inhibitors/metabolism , Adrenergic Uptake Inhibitors/pharmacology , Cell Line , Crystallography, X-Ray , Drug Evaluation, Preclinical/methods , Humans , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Phenols/chemical synthesis , Phenols/metabolism , Phenols/pharmacology , Pyridines/metabolism , Pyridines/pharmacology , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Receptor Agonists/metabolism , Serotonin Receptor Agonists/pharmacologyABSTRACT
Synthesis, pharmacology, and pharmacokinetic profiles of (1R, 2S)-4-(2-cyano-cyclohexyl-oxy)-2-trifluoromethyl-benzonitrile are reported. This compound demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.
Subject(s)
Androgen Antagonists/pharmacology , Hair/growth & development , Hydrocarbons, Fluorinated/pharmacology , Nitriles/pharmacology , Sebum , Animals , Cricetinae , Hydrocarbons, Fluorinated/pharmacokinetics , Male , Mesocricetus , Mice , Models, Molecular , Nitriles/pharmacokineticsABSTRACT
A novel series of conformationally-restricted oxazolidinones was synthesized which possess a fused pyrazole ring substituted with various alkyl, aryl and heteroaryl substituents. A number of analogs exhibited potent activity against both gram-positive and fastidious gram-negative organisms.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Pyrazoles/pharmacology , Molecular Structure , Pyrazoles/chemistry , Structure-Activity RelationshipABSTRACT
Novel 2,4-diaminopyrimidine-based small molecule renin inhibitors are disclosed. Through high throughput screening, parallel synthesis, X-ray crystallography, and structure based drug design, we have developed the first non-chiral, non-peptidic, small molecular template to possess moderate potency against renin. The designed compounds consist of a novel 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-7-yl)pyrimidine-2,4-diamine ring system that exhibit moderate potency (IC(50): 91-650 nM) against renin while remaining 'Rule-of-five' compliant.
Subject(s)
Chemistry, Pharmaceutical/methods , Pyrimidines/chemistry , Renin/antagonists & inhibitors , Animals , Crystallography, X-Ray , Drug Design , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Molecular Conformation , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
We describe a novel class of benzocycloheptanone derived oxazolidinone antibacterial agents. The synthesis and antibacterial activities with structure variation is discussed.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Benzocycloheptenes/chemical synthesis , Benzocycloheptenes/pharmacology , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Anti-Bacterial Agents/chemistry , Benzocycloheptenes/chemistry , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Molecular Structure , Oxazolidinones/chemistry , Structure-Activity RelationshipABSTRACT
Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.
Subject(s)
Factor Xa Inhibitors , Factor Xa/chemistry , Glycine/analogs & derivatives , Glycine/chemistry , Serine Proteinase Inhibitors/chemistry , Crystallography, X-Ray , Humans , Molecular Structure , Protein ConformationABSTRACT
The chemical synthesis of a series of new penam sulfone derivatives bearing a 2beta-substituted-oxyimino and -hydrazone substituents, their beta-lactamase inhibitory properties against selected enzymes representing class A and C beta-lactamases are reported. The oxime containing penam sulfones strongly inhibited the Escherichia coli TEM-1 and Klebsiella pneumoniae cefotaximase (CTX-1) enzymes, but moderately inhibited the Pseudomonas aeruginosa 46012 cephalosporinase; while the 2beta-substituted-hydrazone derivatives were generally less active against these enzymes. Furthermore, most of the inhibitors enhanced the antibacterial activities of piperacillin (PIP) and ceftazidime (CAZ) particularly against TEM-1 and CTX-1 producing bacterial strains.