ABSTRACT
The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that 13-d had properties compatible with oral dosing in mouse models of disease (Fpo 49%). We propose that NI-42 (13-d) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins.
Subject(s)
Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Nuclear Proteins/antagonists & inhibitors , Quinolones/pharmacology , Sulfonamides/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , DNA-Binding Proteins , Drug Screening Assays, Antitumor , Humans , Leukemia, Myeloid, Acute/drug therapy , Mice , Microsomes, Liver/metabolism , Protein Domains , Quinolones/chemical synthesis , Quinolones/chemistry , Quinolones/pharmacokinetics , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacokineticsABSTRACT
The autotaxin-lysophosphatidic acid (ATX-LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties. This has delivered drug-like compounds such as 9v (CRT0273750) which modulate LPA levels in plasma and are suitable for in vivo studies. X-ray crystallography has revealed that these compounds have an unexpected binding mode in that they do not interact with the active site zinc ions but instead occupy the hydrophobic LPC pocket extending from the active site of ATX together with occupying the LPA 'exit' channel.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Lysophospholipase/antagonists & inhibitors , Lysophospholipids/metabolism , Phosphoric Diester Hydrolases/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/pharmacokinetics , Humans , Lysophospholipase/metabolism , Mice , Molecular Docking Simulation , Molecular Targeted Therapy , Neoplasms/drug therapy , Neoplasms/enzymology , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacologyABSTRACT
Abediterol is a novel potent, long-acting inhaled ß(2)-adrenoceptor agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Abediterol shows subnanomolar affinity for the human ß(2)-adrenoceptor and a functional selectivity over ß(1)-adrenoceptors higher than that of formoterol and indacaterol in both a cellular model with overexpressed human receptors and isolated guinea pig tissue. Abediterol is a full agonist at the human ß(2)-adrenoceptor (E(max) = 91 ± 5% of the maximal effect of isoprenaline). The potency and onset of action that abediterol shows in isolated human bronchi (EC(50) = 1.9 ± 0.4 nM; t½ onset = 7-10 min) is not significantly different from that of formoterol, but its duration of action (t½ â¼ 690 min) is similar to that of indacaterol. Nebulized abediterol inhibits acetylcholine-induced bronchoconstriction in guinea pigs in a concentration-dependent manner, with higher potency and longer duration of action (t½ = 36 h) than salmeterol (t½ = 6 h) and formoterol (t½ = 4 h) and similar duration of action to indacaterol up to 48 h. In dogs, the bronchoprotective effect of abediterol is more sustained than that of salmeterol and indacaterol at doses without effects on heart rate, thus showing a greater safety margin (defined as the ratio of dose increasing heart rate by 5% and dose inhibiting bronchospasm by 50%) than salmeterol, formoterol, and indacaterol (5.6 versus 3.3, 2.2, and 0.3, respectively). In conclusion, our results suggest that abediterol has a preclinical profile for once-daily dosing in humans together with a fast onset of action and a favorable cardiovascular safety profile.
Subject(s)
Adrenergic beta-2 Receptor Agonists/pharmacology , Bronchodilator Agents/pharmacology , Receptors, Adrenergic, beta-2/metabolism , Albuterol/analogs & derivatives , Albuterol/pharmacology , Animals , Asthma/drug therapy , Asthma/metabolism , Bronchi/drug effects , Bronchi/metabolism , Bronchoconstriction/drug effects , Dogs , Dose-Response Relationship, Drug , Ethanolamines/pharmacology , Formoterol Fumarate , Guinea Pigs , Humans , Male , Monocytes/drug effects , Monocytes/pathology , Quinolones/pharmacology , Salmeterol XinafoateABSTRACT
A series of pyrido[3',2':4,5]furo[3,2-d]pyrimidines (PFP) were synthesized and tested for phosphodiesterase type 4 (PDE4) inhibitory activity, with the potential to treat asthma and chronic obstructive pulmonary disease (COPD). Structure-activity relationships within this series, leading to an increase of potency on the enzyme, is presented. Both gem-dimethylcyclohexyl moieties fused to the pyridine ring and the substitution at the 5 position of the PFP scaffold, proved to be key elements in order to get a high affinity in the enzyme.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Animals , Asthma/drug therapy , Asthma/enzymology , Caco-2 Cells , Cell Membrane Permeability , Ferrets , Humans , Models, Molecular , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/pharmacokinetics , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/enzymology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Novel quaternary ammonium derivatives of N,N-disubstituted (3R)-quinuclidinyl carbamates have been identified as potent M(3) muscarinic antagonists with long duration of action in an in vivo model of bronchoconstriction. These compounds have also presented a high level of metabolic transformation (human liver microsomes). The synthesis, structure-activity relationships and biological evaluation of these compounds are reported.
Subject(s)
Carbamates/chemical synthesis , Carbamates/pharmacology , Drug Discovery , Microsomes, Liver/drug effects , Muscarinic Antagonists/chemical synthesis , Muscarinic Antagonists/pharmacology , Carbamates/chemistry , Humans , Inhibitory Concentration 50 , Microsomes, Liver/metabolism , Molecular Structure , Muscarinic Antagonists/chemistry , Quaternary Ammonium Compounds/chemical synthesis , Quaternary Ammonium Compounds/chemistry , Quaternary Ammonium Compounds/pharmacology , Quinuclidines/chemical synthesis , Quinuclidines/chemistry , Quinuclidines/pharmacology , Time FactorsABSTRACT
A series of pyrido[3',2':4,5]thieno[3,2-d]pyrimidines (PTP) has been synthesized and tested as phosphodiesterase IV inhibitors (PDE4), a target for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Structure-activity relationships within this series, leading to an increase of potency on the enzyme, are presented. The gem-dimethylcycloalkyl moiety fused to the pyridine ring proved to be a key element of the scaffold in order to get a higher affinity in the enzyme.
Subject(s)
Phosphodiesterase 4 Inhibitors , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Thiophenes/chemical synthesis , Humans , Pichia , Pyridines/chemistry , Pyrimidines/chemistry , Recombinant Proteins/antagonists & inhibitors , Structure-Activity Relationship , Thiophenes/chemistryABSTRACT
The objective of this work was to discover a novel, long-acting muscarinic M(3) antagonist for the inhaled treatment of chronic obstructive pulmonary disease (COPD), with a potentially improved risk-benefit profile compared with current antimuscarinic agents. A series of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters were synthesized and evaluated. On the basis of its overall profile, (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) emerged as a candidate for once-daily maintenance treatment of COPD. This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. Aclidinium bromide is currently in phase III development for maintenance treatment of patients with COPD.
Subject(s)
Muscarinic Antagonists/chemical synthesis , Quaternary Ammonium Compounds/chemical synthesis , Quinuclidines/chemical synthesis , Tropanes/chemical synthesis , Administration, Inhalation , Animals , Bronchial Spasm/drug therapy , Bronchial Spasm/physiopathology , CHO Cells , Cricetinae , Cricetulus , Drug Stability , Esters , Guinea Pigs , Humans , Male , Mice , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Pulmonary Disease, Chronic Obstructive/drug therapy , Quaternary Ammonium Compounds/chemistry , Quaternary Ammonium Compounds/pharmacology , Quinuclidines/chemistry , Quinuclidines/pharmacology , Radioligand Assay , Receptor, Muscarinic M3/physiology , Stereoisomerism , Structure-Activity Relationship , Tropanes/chemistry , Tropanes/pharmacologyABSTRACT
Aclidinium bromide is a novel potent, long-acting inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease. Aclidinium showed subnanomolar affinity for the five human muscarinic receptors (M(1)-M(5)). [(3)H]Aclidinium dissociated slightly faster from M(2) and M(3) receptors than [(3)H]tiotropium but much more slowly than [(3)H]ipratropium. Its association rate for the M(3) receptor was similar to [(3)H]ipratropium and 2.6 times faster than [(3)H]tiotropium. Residence half-life of [(3)H]aclidinium at the M(2) receptor was shorter than at the M(3) receptor, demonstrating kinetic selectivity for the M(3) receptor. In isolated guinea pig trachea, aclidinium showed comparable potency to ipratropium and tiotropium, faster onset of action than tiotropium, and duration of action similar to tiotropium and significantly longer than ipratropium. Nebulized aclidinium inhibited bronchoconstriction induced by acetylcholine in guinea pigs in a concentration-dependent manner with an onset of action faster than tiotropium. Duration of action of aclidinium (t(1/2) = 29 h) was much longer than ipratropium (8 h) but shorter than tiotropium (64 h). In dogs, aclidinium induced a smaller and more transient increase in heart rate than tiotropium at comparable supratherapeutic doses. Therefore, under these conditions, aclidinium showed a greater therapeutic index than tiotropium (4.2 versus 1.6). These results indicate that aclidinium is a potent muscarinic antagonist with a fast onset of action, a long duration of effect, and a favorable cardiovascular safety profile.
Subject(s)
Muscarinic Antagonists/pharmacology , Tropanes/pharmacology , Administration, Inhalation , Anesthesia , Animals , Bronchi/drug effects , Bronchoconstriction/drug effects , CHO Cells , Carbachol/pharmacology , Cricetinae , Cricetulus , Dogs , Guinea Pigs , Heart Rate/drug effects , Humans , Ipratropium/pharmacology , Male , Muscarinic Agonists/pharmacology , Muscarinic Antagonists/administration & dosage , Receptors, Muscarinic/drug effects , Scopolamine Derivatives/pharmacology , Stimulation, Chemical , Tiotropium Bromide , Trachea/drug effects , Tropanes/administration & dosageABSTRACT
A novel series of N-heteroaryl 4'-(2-furyl)-4,5'-bipyrimidin-2'-amines has been identified as potent and selective A(2B) adenosine receptor antagonists. In particular, compound 5 showed high affinity for the A(2B) receptor (Ki = 17 nM), good selectivity (IC(50): A(1) > 1000 nM, A(2A) > 2500 nM, A3 > 1000 nM), displayed a favorable pharmacokinetic profile in preclinical species, and showed efficacy in functional in vitro models.
Subject(s)
Adenosine A2 Receptor Antagonists , Furans/chemical synthesis , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Cell Line , Cricetinae , Cricetulus , Dogs , Furans/pharmacokinetics , Furans/pharmacology , Mice , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Radioligand Assay , Rats , Structure-Activity RelationshipABSTRACT
A new series of 4-(1,3-dialkyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)benzenesulfonamides has been identified as potent A2B adenosine receptor antagonists. The products have been evaluated for their binding affinities for the human A2B, A1 and A3 adenosine receptors. 6-(4-{[4-(4-Bromobenzyl)piperazin-1-yl]sulfonyl}phenyl)-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (16) showed a high affinity for the A2B adenosine receptor (IC50=1 nM) and selectivity (A1: 183x; A3: 12660x). Synthesis and SAR of this novel class of compounds showing improved absorption properties is presented herein.
Subject(s)
Adenosine A2 Receptor Antagonists , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Binding, Competitive , Drug Design , Humans , Inhibitory Concentration 50 , Structure-Activity RelationshipABSTRACT
The synthesis and evaluation as tryptase inhibitors of a library of 2,5-diketopiperazine derivatives containing guanidine or amidine functional groups is reported. Among the compounds evaluated, derivatives 6{CG4-CG8} and 6{CG4-CG9} are the most active compounds and have marked selectivity towards tryptase in front of trypsin.
Subject(s)
Combinatorial Chemistry Techniques/methods , Serine Endopeptidases/chemistry , Models, Chemical , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacology , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Structure-Activity Relationship , TryptasesABSTRACT
The synthesis and structure-activity relationships of piperidinylpyrrolopyridines as potent and selective H(1) antagonists are discussed. It was found that the nature of the acid chain bonded to piperidine was a key feature for maintaining both the duration of action in vivo and lack of sedative properties.
Subject(s)
Histamine H1 Antagonists/chemical synthesis , Pyridines/chemical synthesis , Administration, Oral , Animals , Blood-Brain Barrier , Capillary Permeability , Guinea Pigs , Histamine H1 Antagonists/pharmacokinetics , Histamine H1 Antagonists/pharmacology , Humans , Inhibitory Concentration 50 , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Solubility , Structure-Activity RelationshipABSTRACT
A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H(1) antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT(2) receptor. Extensive optimization was carried out within this series and a number of histamine H(1) antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48,51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation.
Subject(s)
Histamine H1 Antagonists/chemical synthesis , Indoles/chemical synthesis , Piperidines/chemical synthesis , Animals , Blood-Brain Barrier/metabolism , Brain/metabolism , Capillary Permeability/drug effects , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Electrocardiography/drug effects , Guinea Pigs , Half-Life , Histamine H1 Antagonists/pharmacology , Histamine H1 Antagonists/toxicity , Humans , In Vitro Techniques , Indoles/pharmacology , Indoles/toxicity , Male , Mice , Piperidines/pharmacology , Piperidines/toxicity , Radioligand Assay , Rats , Rats, Wistar , Receptors, Adrenergic, alpha-1/drug effects , Receptors, Adrenergic, alpha-1/metabolism , Receptors, Histamine H1/drug effects , Receptors, Histamine H1/metabolism , Receptors, Serotonin/drug effects , Receptors, Serotonin/metabolism , Skin/blood supply , Structure-Activity RelationshipABSTRACT
A series of 2-phenylpyran-4-ones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors were identified. Compounds having a p-methylsulfone group at the 2-phenyl ring showed the best COX-2 inhibitory activity. The introduction of a substituted phenoxy ring at position 3 enhanced both the in vitro and in vivo activity within the series. A selected group of 3-phenoxypyran-4-ones exhibited excellent activity in an experimental model of pyresis. The in vivo antiinflammatory activity of these compounds was confirmed with the evaluation of their antiarthritic and analgesic effectiveness. Moreover, their pharmacokinetic profile in rats is compatible with a once a day administration by oral route in humans. Within this novel series, compounds 21, 31, 34, and 35 have been selected for further preclinical and clinical evaluation.
Subject(s)
Isoenzymes/antagonists & inhibitors , Pyrans/chemical synthesis , Administration, Oral , Animals , Arthritis, Experimental/drug therapy , Blood Proteins/metabolism , Cyclooxygenase 2 , Humans , Hyperalgesia/drug therapy , Male , Membrane Proteins , Prostaglandin-Endoperoxide Synthases , Protein Binding , Pyrans/chemistry , Pyrans/pharmacokinetics , Pyrans/pharmacology , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
The syntheses and SAR studies of various quinazolinone compounds are described for the dual inhibition of Pgp and MRP1 in multidrug resistance.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Drug Resistance, Multiple , Quinazolines/chemical synthesis , Antibiotics, Antineoplastic/antagonists & inhibitors , Antibiotics, Antineoplastic/pharmacokinetics , Antineoplastic Agents/antagonists & inhibitors , Antineoplastic Agents/pharmacokinetics , Daunorubicin/antagonists & inhibitors , Daunorubicin/pharmacokinetics , Doxorubicin/antagonists & inhibitors , Doxorubicin/pharmacokinetics , Drug Interactions , Humans , Inhibitory Concentration 50 , Quinazolines/chemistry , Quinazolines/pharmacology , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A series of pyrazolo[3,4-d]pyridazinones and analogues, potentially useful as peripheral vasodilators, were synthesized and evaluated as inhibitors of PDE5 extracted from human platelets. Several of them showed IC50 values in the range 0.14-1.4 microM. A good activity and selectivity profile versus PDE6 was found for compound 11e (6-benzyl-3-methyl-1-isopropyl-4-phenylpyrazolo[3,4-d] pyridazin-7(6H)-one). Structure-activity relationship studies demonstrated the essential role played by the benzyl group at position-6 of the pyrazolopyridazine system. Other types of pyridazinones fused with five and six membered heterocycles (pyrrole, isoxazole, pyridine and dihydropyridine), as well as some open models were prepared and evaluated. Besides the pyrazole, the best fused systems proved to be isoxazole and pyridine.