ABSTRACT
To discover the best-in-class Bruton's Tyrosine Kinase (BTK) inhibitors, for th treatment of autoimmune disorders like cancer (B-Cell Lymphoma (BCL)) and rheumatoid arthritis (RA), in the present investigation, novel structural optimizations were carried out. Introduction of novel bicyclic amine linkers and aromatic backbone led to series of compounds 9a-h and 14a-u. Compound 14b was found to be potent, orally bioavailable, selective and irreversible BTK inhibitor. In vitro, 14b showed IC50 of 1.0 nM and 0.8 nM, in BTK and TMD8 assays, respectively. In vivo,14b displayed robust efficacy in collagen-induced arthritis (CIA) and TMD8 xenograft models, which could be correlated with its improved oral bioavailability. In the repeated dose acute toxicity study, 14b showed no adverse changes, indicating that the BTK inhibitor 14b could be viable therapeutic option for the treatment of autoimmune disorders.
Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Animals , Humans , Agammaglobulinaemia Tyrosine Kinase , Protein Kinase Inhibitors/chemistry , Amines/pharmacology , Amines/therapeutic use , Arthritis, Experimental/chemically induced , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapyABSTRACT
Selective inhibition of janus kinase (JAK) has been identified as an important strategy for the treatment of autoimmune disorders. Optimization at the C2 and C4-positions of pyrimidine ring of Cerdulatinib led to the discovery of a potent and orally bioavailable 2,4-diaminopyrimidine-5-carboxamide based JAK3 selective inhibitor (11i). A cellular selectivity study further confirmed that 11i preferentially inhibits JAK3 over JAK1, in JAK/STAT signaling pathway. Compound 11i showed good anti-arthritic activity, which could be correlated with its improved oral bioavailability. In the repeat dose acute toxicity study, 11i showed no adverse changes related to gross pathology and clinical signs, indicating that the new class JAK3 selective inhibitor could be viable therapeutic option for the treatment of rheumatoid arthritis.
Subject(s)
Antirheumatic Agents/pharmacology , Arthritis, Experimental/drug therapy , Drug Discovery , Janus Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Animals , Antirheumatic Agents/chemical synthesis , Antirheumatic Agents/chemistry , Arthritis, Experimental/blood , Cell Line , Dose-Response Relationship, Drug , Humans , Janus Kinase 3/blood , Janus Kinase 3/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Molecular Docking Simulation , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
PI3Kδ is implicated in various inflammatory and autoimmune diseases. For the effective treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to develop isoform selective PI3Kδ inhibitors. Structure guided optimization of an imidazo-quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the animal models.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Drug Discovery , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Quinolones/pharmacology , Class I Phosphatidylinositol 3-Kinases/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Structure , Phosphoinositide-3 Kinase Inhibitors/chemical synthesis , Phosphoinositide-3 Kinase Inhibitors/chemistry , Quinolones/chemical synthesis , Quinolones/chemistry , Structure-Activity RelationshipABSTRACT
TGR5 is a member of G protein-coupled receptor (GPCR) superfamily, a promising molecular target for metabolic diseases. Activation of TGR5 promotes secretion of glucagon-like peptide-1 (GLP-1), which activates insulin secretion. A series of 2-thio-imidazole derivatives have been identified as novel, potent and orally efficacious TGR5 agonists. Compound 4d, a novel TGR5 agonist, in combination with Sitagliptin, a DPP-4 inhibitor, has demonstrated an adequate GLP-1 secretion and glucose lowering effect in animal models, suggesting a potential clinical option in treatment of type-2 diabetes.
Subject(s)
Hypoglycemic Agents/chemistry , Imidazoles/chemistry , Receptors, G-Protein-Coupled/agonists , Animals , Binding Sites , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/veterinary , Drug Therapy, Combination , Female , Glucagon-Like Peptide 1/metabolism , Half-Life , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Imidazoles/pharmacokinetics , Imidazoles/therapeutic use , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Protein Structure, Tertiary , Receptors, G-Protein-Coupled/metabolism , Sitagliptin Phosphate/therapeutic use , Structure-Activity RelationshipABSTRACT
DPP-IV "a moonlighting protein" has immerged as promising pathway to control Type 2 diabetes as well as found to play key role in earlier stages of cancer. Here we have reported design, synthesis and applications of aminocoumarin derivatives as DPP-IV inhibitors. Compounds have been synthesized and studied for their DPP-IV inhibition activity. Three compounds have shown moderate inhibition at 100⯵M concentration. All compounds were also screened for their anticancer activity against A549 (Lung cancer cell line), MCF-7 (Breast cancer cell line) using MTT assay. One of the compounds has shown very good anticancer activity with IC50 value 24⯱â¯0.1â¯nM against A549 cell line.
Subject(s)
Aminocoumarins/pharmacology , Antineoplastic Agents/pharmacology , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Drug Design , Aminocoumarins/chemical synthesis , Aminocoumarins/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , MCF-7 Cells , Molecular Structure , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
Herein we report design, synthesis, and anticancer activity of compounds 6a-h and 11a-j. Compounds 6a-f were designed based on 3-aminomethyl pyridine attached to different acetamide derivatives and in compounds 6g-h it was attached to coumarin moiety. Coumarin containing compounds 6g-h showed very poor anticancer activity against both A549 (Lungs cancer cell line), and MCF-7 (Breast cancer cell line) cell lines in MTT assay. Compounds 11a-j were designed as derivatives of 3-aminomethyl pyridine and 4-amino chalcones. A series of chalcone derivatives of 3-aminomethyl pyridine 11a-j have been synthesized and screened for their in vitro anticancer activity and DNA binding affinity. Most of the compounds showed very good antimitotic activity against A549 cell line as compared to fluorouracil. Compounds 11g and 11i were selected for DNA-binding studies as they showed excellent activity against cancer cell lines in MTT assay. CT-DNA binding affinity of compounds 11g and 11i have been investigated by UV based DNA titration and fluorescence emission study against DNA-EtBr complex. Interestingly, compound 11i has displayed excellent antiproliferative activity, with IC50 0.0067 ± 0.0002 µm, against MCF-7 cell line. Compound 11i has been studied for its cytotoxicity using MTT, LDH, as well as EtBr/AO assay and was found to induce apoptosis in the cancerous cell line.
Subject(s)
Antineoplastic Agents/chemistry , Chalcones/chemistry , DNA/chemistry , Drug Design , A549 Cells , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Chalcones/metabolism , Chalcones/pharmacology , DNA/metabolism , Drug Screening Assays, Antitumor , Humans , MCF-7 Cells , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
Type 2 diabetes (T2D) is a lifestyle disease affecting millions of people worldwide. Various therapies are available for the management of T2D and dipeptidyl peptidase-IV (DPP-IV) inhibition has emerged as a promising therapy for the treatment of type 2 diabetes (T2D). Here we report design, synthesis and in vitro efficacy of sulfonamide derivatives of pyrrolidine and piperidine as anti-diabetic agents. Amongst all the compounds synthesized in this series, 9a, is the most potent (IC50 = 41.17 nM).
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Drug Design , Hypoglycemic Agents/therapeutic use , Piperidines/therapeutic use , Pyrrolidines/therapeutic use , Sulfonamides/therapeutic use , Dose-Response Relationship, Drug , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Molecular Docking Simulation , Molecular Structure , Piperidines/chemistry , Pyrrolidines/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistryABSTRACT
We have synthesized various amide derivatives of benzodifuran-2-carboxylic acid from resorcinol. Reaction of 7-hydroxy-4-methylcoumarin with chloroacetone in anhydrous K2CO3 and dry acetone gave ether derivative of 7-hydroxy-4-methylcoumarin 3 which on reaction with N-bromosuccinimide in chloroform gave corresponding 3-bromo derivative 4. Cyclization of bromo derivative in 10% ethanolic KOH gave benzodifuran-2-carboxylic acid 5. This acid was converted into acid chloride using oxalyl chloride and then substituted with different amines in presence of base, triethylamine to give amide derivatives of benzodifuran-2-carboxylic acid 6. All compounds were screened for antimicrobial activity against two Gram positive bacteria Staphylococus aureus and Bacillus subtilis, two Gram negative bacteria E. coli and P. aeruginosa and one fungus Candida albicans.