ABSTRACT
Designing drug candidates exhibiting polypharmacology is one of the strategies adopted by medicinal chemists to address multifactorial diseases. Metabolic disease is one such multifactorial disorder characterized by hyperglycaemia, hypertension and dyslipidaemia among others. In this paper we report a new class of molecular framework combining the pharmacophoric features of DPP4 inhibitors with those of ACE inhibitors to afford potent dual inhibitors of DPP4 and ACE.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Metabolic Syndrome/drug therapy , Angiotensin-Converting Enzyme Inhibitors/chemistry , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dogs , Humans , Inhibitory Concentration 50 , Mice , Microsomes, Liver/drug effects , Molecular Docking Simulation , RatsABSTRACT
Pharmacological intervention of epidermal growth factor receptor (EGFR) family members by antibodies or small molecule inhibitors has been one of the most successful approaches for anticancer therapy. However this therapy has its own limitations due to the development of resistance, over a period of time. One of the possible causes of the development of resistance to the therapy with EGFR inhibitors could be the simultaneous activation of parallel pathways. Both EGFR and insulin like growth factor-1 receptor (IGF-1R) pathways are reported to act reciprocal to each other and converge into the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. Inhibiting one pathway alone may therefore not be sufficient and could be a cause of development of resistance. The other cause could be mutations of EGFR which would be less sensitive to the inhibitors. We, therefore, suggest that co-targeting IGF-1R and EGFR kinases by dual inhibitors can lead to improved efficacy and address the problems of resistance. In the present manuscript, we report the identification of a novel, small molecule dual EGFR/IGF-1R inhibitor, RBx10080307 which displayed in vitro activity at the molecular level and oral efficacy in mouse xenograft model. The compound also showed in vitro activity in an EGFR mutant cell line and may thus have the potential to show activity in resistant conditions. Additional efficacy studies are needed in EGFR resistant mouse cancer model and if found efficacious, this can be a major advantage over standalone erlotinib and other existing therapies.
Subject(s)
Antineoplastic Agents/pharmacology , ErbB Receptors/antagonists & inhibitors , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Animals , Antineoplastic Agents/metabolism , Apoptosis/drug effects , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/drug effects , Drug Stability , ErbB Receptors/genetics , ErbB Receptors/metabolism , Erlotinib Hydrochloride , Female , HT29 Cells , Humans , Male , Membrane Potential, Mitochondrial/drug effects , Mice , Microsomes, Liver/metabolism , Mutation , Phosphorylation/drug effects , Piperazine , Piperazines/metabolism , Protein Kinase Inhibitors/metabolism , Pyrazoles/metabolism , Pyrimidines/metabolism , Quinazolines/pharmacology , Receptor, IGF Type 1/metabolism , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysABSTRACT
A novel set of compounds containing a 4,5-dihydro-5-methylisoxazoline have been successfully designed as VLA-4 receptor antagonists. Compound (14p) had a high receptor binding affinity of 4 nM and also found to be metabolically stable in vitro.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Isoxazoles/chemistry , Isoxazoles/pharmacology , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Drug Stability , Humans , Integrin alpha4beta1/chemistry , Isoxazoles/chemical synthesis , Protein Binding , Structure-Activity Relationship , U937 CellsABSTRACT
The synthesis and antibacterial activity of 1,2,4-triazolo[4,3-a]pyrimidine oxazolidinones is reported. Compound 3e with a 2,4-disubstituted thiophene ring was found to be a potent inhibitor of Gram-positive pathogens and was 4-16-fold more potent than Linezolid.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Gram-Positive Bacteria/drug effects , Oxazolidinones/pharmacology , Pyrimidines/pharmacology , Triazoles/pharmacology , Anti-Bacterial Agents/chemistry , Chemistry Techniques, Synthetic , Dose-Response Relationship, Drug , Models, Molecular , Molecular Structure , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
The synthesis and antibacterial activity of 3-(4-([1,2,4]triazolo[4,3-a]pyrimidin-3-yl)phenyl)oxazolidin-2-ones is reported. Thiocarbonyl derivatives were found to be potent inhibitors of gram-positive pathogens and compound 4l was two to fourfold more potent than Linezolid.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Gram-Positive Bacteria/drug effects , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Pyrimidines/chemical synthesis , Acetamides/chemistry , Acetamides/pharmacology , Anti-Bacterial Agents/chemistry , Linezolid , Microbial Sensitivity Tests , Molecular Structure , Oxazolidinones/chemistry , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship , Thiocarbamates/chemistry , Thiocarbamates/pharmacologyABSTRACT
RBx 343E48F0 is a novel, potent, selective and long acting muscarinic receptor antagonist with a potential for use in the treatment of Chronic Obstructive Pulmonary Disease (COPD). The aim of the present study was to describe the in vitro and in vivo profile of RBx 343E48F0 and to compare the results with the present day benchmark therapy, tiotropium. Radioligand binding and isolated tissue based functional assays were used to evaluate the affinity, potency and receptor subtype selectivity of RBx 343E48F0. Inhibition of carbachol-induced bronchoconstriction in the anaesthetized rat and acetylcholine-induced bronchoconstriction in the conscious rat were used to assess the extent and duration of the bronchospasmolytic activity of RBx 343E48F0. In vitro and in vivo pharmacokinetic studies were conducted to evaluate the pharmacokinetic and lung retention properties of the compound. In vitro radioligand binding studies using human recombinant muscarinic receptors showed that RBx 343E48F0 had a pKi of 9.6 at the M(3) receptor and a 60-fold selectivity for the M(3) receptor over the M(2) receptor. In isolated tissue bioassays, it exhibited surmountable antagonism at the guinea pig trachea with a pK(B) of 9.5. Intratracheal administration to anaesthetized rats demonstrated a dose-dependent inhibition of carbachol-induced bronchoconstriction with an ED(50) value of 110 ng/kg. RBx 343E48F0 also exhibited a fast onset of action and long duration of action of greater 24h.
Subject(s)
Imidazoles/pharmacology , Imidazoles/pharmacokinetics , Muscarinic Antagonists/pharmacology , Muscarinic Antagonists/pharmacokinetics , Receptors, Muscarinic/metabolism , Acetylcholine/pharmacology , Animals , Bronchoconstriction/drug effects , Female , Guinea Pigs , Humans , Imidazoles/administration & dosage , Imidazoles/metabolism , Methacholine Chloride/pharmacology , Muscarinic Antagonists/administration & dosage , Muscarinic Antagonists/metabolism , Rats , Respiration, Artificial , Substrate SpecificityABSTRACT
A novel set of compounds with a 1,3-dioxolane ring which acts as a proline bioisostere have been successfully designed as VLA-4 receptor antagonists. Compounds (18e), (28j), and (35g) were shown to have high receptor affinities.
Subject(s)
Dioxolanes/chemistry , Dioxolanes/pharmacology , Integrin alpha4beta1/antagonists & inhibitors , Integrin alpha4beta1/metabolism , Cell Line , Dioxolanes/chemical synthesis , Humans , Models, Molecular , Protein Binding/drug effects , Structure-Activity RelationshipABSTRACT
The Ser/Thr protein kinase MAPKAP kinase2 (MAPKAPK2 or MK2) plays an important role in inflammation. A comparison of several crystal structures of MK2 shows that differences in active and inactive conformations result in large part from structural variations within the conformations of the glycine rich loop (p-loop) regions. We propose the most preferred binding conformation of two classes of MK2 inhibitors and suggest plausible critical interactions with active site residues. The predicted binding conformations of the two classes of MK2 inhibitors depend upon their orientation in the active site and activities were well correlated with the sum of D and G scores. A qualitative relationship between the sum of D and G scores and the measured activities can be demonstrated.
Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/chemistry , Models, Molecular , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/chemistry , Pyrazoles/metabolism , Pyrazoles/pharmacology , Pyridines/metabolism , Pyridines/pharmacology , Adenosine Triphosphate/metabolism , Amino Acid Motifs , Amino Acid Sequence , Catalytic Domain , Computer Simulation , Conserved Sequence , Crystallography, X-Ray , Glycine , Intracellular Signaling Peptides and Proteins/metabolism , Ligands , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Secondary , Pyrazoles/chemistry , Pyridines/chemistry , Reproducibility of ResultsABSTRACT
A series of pyrazolo[3,4-d]pyrimidine, pyrrolo[2,3-d]pyrimidine and 6-arylpurine adenosine A(2A) antagonists is described. Many examples were highly selective against the human A(1) receptor sub-type and were active in an in vivo model of Parkinson's disease.
Subject(s)
Adenosine A2 Receptor Antagonists , Antiparkinson Agents/therapeutic use , Drug Design , Parkinsonian Disorders/drug therapy , Purines/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenosine A1 Receptor Antagonists , Antiparkinson Agents/chemical synthesis , Humans , Models, Chemical , Purines/chemical synthesis , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We describe herein the discovery and development of a series of 4-arylthieno[3,2-d]pyrimidines which are potent adenosine A(2A) receptor antagonists. These novel compounds show high degrees of selectivity against the human A(1), A(2B) and A(3) receptor sub-types. Moreover, a number of these compounds show promising activity in vivo, suggesting potential utility in the treatment of Parkinson's disease.
Subject(s)
Adenosine A2 Receptor Antagonists , Antiparkinson Agents/therapeutic use , Drug Design , Parkinsonian Disorders/drug therapy , Pyrimidines/therapeutic use , Adenosine A1 Receptor Antagonists , Adenosine A3 Receptor Antagonists , Antiparkinson Agents/chemical synthesis , Humans , Models, Chemical , Pyrimidines/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The (-)-(11R,2'S)-enantiomer of the antimalarial drug mefloquine has been found to be a reasonably potent and moderately selective adenosine A(2A) receptor antagonist. Further investigation of this compound has led to the discovery of a series of keto-aryl thieno[3,2-d]pyrimidine derivatives, which are potent and selective antagonists of the adenosine A(2A) receptor. These derivatives show selectivity against the A(1) receptor. Furthermore, some of these compounds have been shown to have in vivo activity in a commonly used model, suggesting the potential for the treatment of Parkinson's disease.
Subject(s)
Adenosine A2 Receptor Antagonists , Antimalarials/therapeutic use , Antiparkinson Agents/therapeutic use , Parkinsonian Disorders/drug therapy , Pyrimidines/therapeutic use , Antimalarials/chemical synthesis , Antiparkinson Agents/chemical synthesis , Humans , Models, Chemical , Pyrimidines/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Several potent oxazolidinone antibacterial agents were obtained by systematic modification of the linker between the five-membered heterocycle and the piperazinyl ring of RBx 7644 (Ranbezolid, 1) and its thienyl analogue 2, leading to the identification of an expanded spectrum compound RBx 8700 (6b).
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Anti-Bacterial Agents/chemistry , Enterococcus faecium/drug effects , Molecular Structure , Oxazolidinones/chemistry , Staphylococcus aureus/drug effects , Streptococcus pyogenes/drug effects , Structure-Activity RelationshipABSTRACT
A series of constrained piperidine analogues were synthesized as novel muscarinic M(3) receptor antagonists. Evaluation of these compounds in binding assays revealed that they not only have high affinity for the M(3) receptor but also have high selectivity over the M(2) receptor.
Subject(s)
Muscarinic Antagonists/chemical synthesis , Muscarinic Antagonists/pharmacology , Receptor, Muscarinic M3/antagonists & inhibitors , Muscarinic Antagonists/chemistry , Structure-Activity RelationshipABSTRACT
A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.