ABSTRACT
The Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase first identified as the product of a gene rearrangement in Anaplastic Large Cell Lymphoma. ALK has subsequently been found to be rearranged, mutated, or amplified in a further series of tumours including neuroblastoma, and Non-Small Cell Lung Cancer. There is strong preclinical evidence that ALK is a driving force for oncogenesis in these cases, and that inhibition of ALK kinase activity results in anti-tumoural efficacy. These observations have sparked the development of small molecule kinase inhibitors, the most advanced of which is currently in clinical testing and which has shown promising preliminary activity in the subset of lung cancer patients whose tumours harbour activated ALK. In this review, we describe the various oncogenic forms of ALK, relevant clinical settings, and give a detailed overview of current drug discovery efforts in the field.
Subject(s)
Genetic Predisposition to Disease/genetics , Mutation , Neoplasms/genetics , Protein-Tyrosine Kinases/genetics , Anaplastic Lymphoma Kinase , Animals , Crizotinib , Humans , Molecular Structure , Neoplasms/drug therapy , Neoplasms/enzymology , Piperidines/chemistry , Piperidines/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Pyrazoles , Pyridines/chemistry , Pyridines/therapeutic use , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Pyrroles/chemistry , Pyrroles/therapeutic use , Receptor Protein-Tyrosine KinasesABSTRACT
A new class of compounds combining thromboxane-A2 (TxA2) receptor antagonism and thromboxane synthase inhibition is described. A first series of (E)- and (Z)-[[[2-(1H-imidazol-1-yl)ethylidene]amino]oxy]pentanoic acids showed relevant thromboxane synthase inhibition associated with weak TxA2 receptor antagonism, while a series of (+/-)-(E)-[[[2-(1H-imidazol-1-yl)-3-phenylpropylidene]amino]oxy] pentanoic acids, structurally derived from the former, showed potent and well-balanced dual activity. Structural requirements for significant single and dual activity are discussed. Two close congeners of the latter series, (+/-)-(E)-5-[[[1-cyclohexyl-2-(1H-imidazol-1-yl)-3- phenylpropylidene]amino]oxy]pentanoic acid 23c and its p-fluorophenyl analog 23m, inhibited TxB2 production in vitro, in rat whole blood during clotting, with IC50 of 0.06 and 0.37 microM and antagonized the binding of [3H]SQ 29548 to washed human platelets, with IC50 of 0.08 and 0.02 microM, respectively. These two compounds were selected for further pharmacological evaluation and were shown to antagonize U46619-induced platelet aggregation in human platelet rich plasma with IC50 of 0.30 and 0.44 microM, respectively. They were both orally available, and in particular 23m caused a long lasting ex vivo TxA2 synthase inhibition in the fed rat. The levorotatory enantiomer of 23c, stereospecifically synthesized as a model compound, was found to be more potent than racemic 23c with regard to TxA2 receptor antagonism (IC50 = 0.04 microM) and equivalent to the latter with regard to TxA2 synthase inhibition. A molecular modeling study concerning the levorotatory enantiomer of 23c (S), TxA2, and representative TxA2 antagonists of different classes led to the definition of a putative pharmacophoric model for the TxA2 receptor ligands.
Subject(s)
Imidazoles/chemical synthesis , Pentanoic Acids/chemical synthesis , Receptors, Thromboxane/antagonists & inhibitors , Thromboxane-A Synthase/antagonists & inhibitors , 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid , Animals , Binding, Competitive , Blood Platelets/drug effects , Blood Platelets/metabolism , Bridged Bicyclo Compounds, Heterocyclic , Computer Simulation , Dogs , Fatty Acids, Unsaturated , Fibrinolytic Agents , Humans , Hydrazines/blood , Imidazoles/chemistry , Imidazoles/pharmacology , Male , Models, Molecular , Molecular Structure , Pentanoic Acids/chemistry , Pentanoic Acids/pharmacology , Platelet Aggregation/drug effects , Prostaglandin Endoperoxides, Synthetic/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Thromboxane A2/analogs & derivatives , Thromboxane A2/pharmacology , Thromboxane B2/antagonists & inhibitorsABSTRACT
A series of derivatives of 4-phenyl-1,4-dihydropyridine bearing imidazol-1-yl or pyridin-3-yl moieties on the phenyl ring were synthesized with the aim of combining Ca2+ antagonism and thromboxane A2 (TxA2) synthase inhibition in the same molecule. Some of these compounds showed significant combined Ca2+ antagonism and TxA2 synthase inhibition in vitro, while others showed only one single activity. Structural requirements for significant single or combined activities are discussed. Theoretical conformational analysis, by molecular mechanics and semiempirical AM1 calculations, was performed for 1,4-dihydro-2,6-dimethyl-4-[3-(1H-imidazol-1-yl)phenyl]- 3,5-pyridinedicarboxylic acid, diethyl ester (FCE 24265) and two close congeners. FCE 24265, which inhibited TxB2 production in rat whole blood with IC50 = 1.7 x 10(-7) M and antagonized K+ induced contraction in guinea pig aorta with IC50 = 6.0 x 10(-8) M, was selected for further pharmacological evaluation. Our results show that this compound is less potent than nifedipine both in vitro and in vivo yet presents a favorable profile in vivo, lowering blood pressure without inducing reflex tachycardia. Moreover, its additional potent and selective TxA2 synthase inhibitory activity makes this compound an interesting pharmacologic tool in pathologies where both enhanced TxA2 synthesis and cellular Ca2+ overload are involved.
Subject(s)
Calcium/antagonists & inhibitors , Dihydropyridines/chemical synthesis , Imidazoles/chemical synthesis , Pyridines/chemical synthesis , Thromboxane-A Synthase/antagonists & inhibitors , Animals , Blood Pressure/drug effects , Dihydropyridines/pharmacology , Dogs , Guinea Pigs , Ileum/physiology , Imidazoles/pharmacology , Male , Molecular Structure , Muscle Contraction/drug effects , Muscle, Smooth/physiology , Myocardial Contraction/drug effects , Nifedipine/pharmacology , Potassium/pharmacology , Pyridines/pharmacology , Rabbits , Rats , Structure-Activity RelationshipABSTRACT
Condensation between furyllithium reagents and pyrimidinones 1, 2, 3, and 4 has been studied. The product composition is strongly dependent upon the reaction conditions and purification methodologies. Cytostatic and antiviral activities of some substrates and reaction products is reported.
