ABSTRACT
In this paper synthesis of macrolones 1-18 starting from azithromycin is reported. Two key steps in the construction of the linker between macrolide and quinolone moiety, are formation of central ether bond by alkylation of unactivated OH group, and formation of terminal C-C bond at 6-position of the quinolone unit. Due to the difficulty in formation of these two bonds the study of alternative synthetic methodologies and optimization of the conditions for the selected routes was required. Formation of C-4''-O-ether bond was completed by modified Michael addition, whereas O-alkylation via diazonium cation proved to be the most effective in formation of the central allylic or propargylic ether bond. Comparison of Heck and Sonogashira reaction revealed the former as preferred route to the C-C bond formation at C(6) position of the quinolone unit. Most of the target compounds exhibited highly favorable antibacterial activity against common respiratory pathogens, without significant cytotoxicity profile when tested in vitro on eukaryotic cell lines.
Subject(s)
Azithromycin/analogs & derivatives , Cross-Linking Reagents/chemistry , Ethers/chemistry , Macrolides/chemistry , Cross-Linking Reagents/chemical synthesis , Ethers/chemical synthesis , Humans , Macrolides/chemical synthesis , Models, Chemical , Molecular StructureABSTRACT
Optimisation of a series of oxazole diketopiperazines has led to the discovery of a very potent and selective oxytocin antagonist GSK221149A. GSK221149A has been shown to inhibit oxytocin-induced uterine contractions in the anaesthetised rat.
Subject(s)
Oxytocin/antagonists & inhibitors , Piperazines/chemistry , Piperazines/pharmacology , Animals , Female , Humans , Kinetics , Oxytocin/metabolism , Piperazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptors, Oxytocin/metabolism , Structure-Activity Relationship , Uterine Contraction/drug effectsABSTRACT
Spontaneous and induced uterine contractions in the rat were found to be inhibited by a novel and selective oxytocin receptor antagonist GSK221149A (3R,6R)-3-Indan-2-yl-1-[(1R)-1-(2-methyl-1,3-oxazol-4-yl)-2-morpholin-4-yl-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione. GSK221149A displayed nanomolar affinity (K(i) = 0.65 nM) for human recombinant oxytocin receptors with >1,400-fold selectivity over human V1a, V1b, and V2 receptors. GSK221149A had similar affinity (K(i) = 4.1 nM) and selectivity for native oxytocin receptors from rat and produced a functional, competitive block of oxytocin-induced contractions in isolated rat myometrial strips with a pA(2) value of 8.18. Intravenous administration of GSK221149A produced a dose-dependent decrease in oxytocin-induced uterine contractions in anesthetized rats with an ID(50) = 0.27 +/- 0.60 mg/kg (corresponding plasma concentrations were 88 ng/ml). Oral administration of GSK221149A (5 mg/kg) was effective in inhibiting oxytocin-induced uterine contractions after single and multiple (4-day) dosing. Spontaneous uterine contractions in late-term pregnant rats (19-21 days gestation) were significantly reduced by intravenous administration of 0.3 mg/kg of GSK221149A. These results provide further evidence that selective oxytocin receptor antagonism may offer an effective treatment for preterm labor.
Subject(s)
Oxytocin/antagonists & inhibitors , Oxytocin/pharmacology , Piperazines/pharmacology , Receptors, Oxytocin/antagonists & inhibitors , Uterine Contraction/physiology , Anesthesia , Animals , Binding, Competitive/drug effects , CHO Cells , Cell Line , Cricetinae , Cricetulus , Female , Humans , Parity , Pregnancy , Rats , Rats, Sprague-Dawley , Receptors, Vasopressin/drug effects , Transfection , Vasopressins/pharmacologyABSTRACT
The discovery, synthesis and structure-activity relationship (SAR) of novel carboxylic acid agonists for GPR40 are described. Aryl propionic acid 1, identified from a high throughput screen, was selected for chemical exploration. Compound 2 was identified as our lead molecule through efficient solid phase combinatorial array chemistry and had an attractive in vitro and in vivo pharmacokinetic profile in rat. These ligands may prove useful in establishing a role for GPR40 in insulin regulation.
Subject(s)
Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Biological Availability , CHO Cells , Carboxylic Acids/pharmacokinetics , Chemical Phenomena , Chemistry, Physical , Cricetinae , Cricetulus , Drug Evaluation, Preclinical , Indicators and Reagents , Ligands , Protein Binding , Rats , Structure-Activity RelationshipABSTRACT
A novel series of pyrazolo[3,4-b]pyridines has been identified that are potent inhibitors of glycogen synthase kinase-3 (GSK-3).
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyridines/chemical synthesis , Glycogen Synthase Kinase 3/chemistry , Pyrazoles/chemistry , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
Introduction of a nitrogen atom into the 6-position of a series of pyrazolo[3,4-b]pyridines led to a dramatic improvement in the potency of GSK-3 inhibition. Rationalisation of the binding mode suggested participation of a putative structural water molecule, which was subsequently confirmed by X-ray crystallography.
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyridazines/chemical synthesis , Models, Molecular , Pyrazoles/chemistry , Pyridazines/chemistry , Structure-Activity RelationshipABSTRACT
Modification of the pyrimidone 5-substituent in clinical candidate SB-435495 has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency. Cyclopentyl fused derivative 21, SB-480848, showed an enhanced in vitro and in vivo profile versus SB-435495 and has been selected for progression to man.
Subject(s)
Enzyme Inhibitors/pharmacology , Phospholipases A/antagonists & inhibitors , Pyrimidinones/pharmacology , 1-Alkyl-2-acetylglycerophosphocholine Esterase , Animals , Cytochrome P-450 CYP2D6 Inhibitors , Enzyme Inhibitors/chemistry , Humans , In Vitro Techniques , Kinetics , Phospholipases A/blood , Phospholipases A2 , Pyrimidinones/chemistry , Rabbits , Recombinant Proteins/antagonists & inhibitorsABSTRACT
The introduction of a functionalised amido substituent into a series of 1-(biphenylmethylacetamido)-pyrimidones has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency and very encouraging developability properties. Diethylaminoethyl derivative 32, SB-435495, was selected for progression to man.
Subject(s)
Biphenyl Compounds/pharmacology , Enzyme Inhibitors/pharmacology , Lipoproteins/metabolism , Phospholipases A/antagonists & inhibitors , Pyrimidinones/pharmacology , Administration, Oral , Animals , Biphenyl Compounds/administration & dosage , Biphenyl Compounds/chemistry , Biphenyl Compounds/metabolism , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Humans , Phospholipases A/metabolism , Pyrimidinones/administration & dosage , Pyrimidinones/chemistry , Pyrimidinones/metabolism , Rabbits , Structure-Activity RelationshipABSTRACT
A series of 1-(biphenylmethylamidoalkyl)-pyrimidones has been designed as nanomolar inhibitors of recombinant lipoprotein-associated phospholipase A(2) with high potency in whole human plasma. 5-(Pyrazolylmethyl) derivative 16 and 5-(methoxypyrimidinylmethyl) derivative 27 demonstrated excellent pharmacodynamic profiles which correlated well with their pharmacokinetic effects.