RESUMO
An efficient synthesis of 2-substituted O(4)-cyclohexylmethyl-5-nitroso-6-aminopyrimidines from 6-amino-2-mercaptopyrimidin-4-ol has been developed and used to prepare a range of derivatives for evaluation as inhibitors of cyclin-dependent kinase 2 (CDK2). The structure-activity relationships (SARs) are similar to those observed for the corresponding O(6)-cyclohexylmethoxypurine series with the 2-arylsulfonamide and 2-arylcarboxamide derivatives showing excellent potency. Two compounds, 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2-hydroxyethyl)benzenesulfonamide (7q) and 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7s), were the most potent with IC50 values of 0.7 +/- 0.1 and 0.8 +/- 0.0 nM against CDK2, respectively. The SARs determined in this study are discussed with reference to the crystal structure of 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7j) bound to phosphorylated CDK2/cyclin A.
Assuntos
Química Farmacêutica/métodos , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Cicloexanos/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Trifosfato de Adenosina/química , Cristalização , Ciclina A/metabolismo , Cicloexanos/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cinética , Modelos Químicos , Modelos Moleculares , Relação Estrutura-Atividade , Sulfonamidas/química , BenzenossulfonamidasRESUMO
Cyclin dependent kinases are a key family of kinases involved in cell cycle regulation and are an attractive target for cancer chemotherapy. The roles of four residues of the cyclin-dependent kinase active site in inhibitor selectivity were investigated by producing cyclin-dependent kinase 2 mutants bearing equivalent cyclin-dependent kinase 4 residues, namely F82H, L83V, H84D, and K89T. Assay of the mutants with a cyclin-dependent kinase 4-selective bisanilinopyrimidine shows that the K89T mutation is primarily responsible for the selectivity of this compound. Use of the cyclin-dependent kinase 2-selective 6-cyclohexylmethoxy-2-(4'-sulfamoylanilino)purine (NU6102) shows that K89T has no role in the selectivity, while the remaining three mutations have a cumulative influence. The results indicate that certain residues that are not frequently considered in structure-aided kinase inhibitor design have an important role to play.
Assuntos
Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Sequência de Aminoácidos , Cristalografia por Raios X , Quinase 2 Dependente de Ciclina/química , Quinase 2 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/química , Quinase 4 Dependente de Ciclina/genética , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Mutagênese Sítio-Dirigida , Mutação , Ligação Proteica , Purinas/químicaRESUMO
Protein kinases are attractive targets for rational drug design against a wide range of diseases. From detailed knowledge of the structure-function relationships underlying protein kinase activity and regulation, a number of methods for achieving kinase inhibition have been suggested and explored using structure-aided drug discovery. Attaining selective protein kinase inhibition in a cellular context, and converting the large number of known potent kinase inhibitors into effective drugs, are outstanding problems in this area and, from a structural perspective, the challenges presented by modulating pharmacokinetics and minimizing the incidence of resistant mutations in the target are of particular interest.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Desenho de Fármacos , Estrutura Molecular , Proteínas Quinases/efeitos dos fármacos , Humanos , Peso Molecular , Inibidores de Proteínas Quinases , Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
The adenosine 5'-triphosphate (ATP) competitive cyclin-dependent kinase inhibitor O(6)-cyclohexylmethylguanine (NU2058, 1) has been employed as the lead in a structure-based drug discovery program resulting in the discovery of the potent CDK1 and -2 inhibitor NU6102 (3, IC(50) = 9.5 nM and 5.4 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). The SAR for this series have been explored further by the synthesis and evaluation of 45 N(2)-substituted analogues of NU2058. These studies have confirmed the requirement for the hydrogen bonding N(2)-NH group and the requirement for an aromatic N(2)-substituent to confer potency in the series. Additional potency is conferred by the presence of a group capable of donating a hydrogen bond at the 4'-position, for example, the 4'-hydroxy derivative (25, IC(50) = 94 nM and 69 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), 4'-monomethylsulfonamide derivative (28, IC(50) = 9 nM and 7.0 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), and 4'-carboxamide derivative (34, IC(50) = 67 nM and 64 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). X-ray crystal structures have been obtained for key compounds and have been used to explain the observed trends in activity.
Assuntos
Proteína Quinase CDC2/antagonistas & inibidores , Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Cicloexanos/síntese química , Guanina/análogos & derivados , Guanina/síntese química , Purinas/síntese química , Animais , Proteína Quinase CDC2/química , Quinases relacionadas a CDC2 e CDC28/química , Cristalografia por Raios X , Quinase 2 Dependente de Ciclina , Cicloexanos/química , Guanina/química , Humanos , Modelos Moleculares , Purinas/química , Purinas/farmacologia , Estrelas-do-Mar , Relação Estrutura-AtividadeRESUMO
A series of O(4)-cyclohexylmethyl-5-nitroso-6-aminopyrimidines bearing 2-arylamino substituents was synthesised and evaluated for CDK1 and CDK2 inhibitory activity. Consistent with analogous studies with O(6)-cyclohexylmethylpurines, 2-arylaminopyrimidines with a sulfonamide or carboxamide group at the 4'-position were potent inhibitors, with IC(50) values against CDK2 of 1.1+/-0.3 and 34+/-8 nM, respectively. The crystal structure of the 4'-carboxamide derivative, in complex with phospho-Thr160 CDK2/cyclin A, confirmed the expected binding mode of the inhibitor, and revealed an additional interaction between the carboxamide function and an aspartate residue.
Assuntos
Proteína Quinase CDC2/antagonistas & inibidores , Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Desenho de Fármacos , Pirimidinas/síntese química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Quinase 2 Dependente de Ciclina , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ligação Proteica , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: To detail specific effects of long-acting risperidone on individuals with schizophrenia and their way of life in a series of four cases. METHOD: Four patients with schizophrenia were selected from four different psychiatric centres. Patients were established on an oral dose of risperidone (1-4 mg/day) for 2 weeks. Based on their oral dose, they then received intramuscular injections of 25 mg or 50 mg of long-acting risperidone every 2 weeks, which could be adjusted according to clinical response. Assessments of efficacy (Positive And Negative Syndrome Scale, Clinical Global Impression-Severity) and safety (Extrapyramidal Symptom Rating Scale) were made at intervals throughout a 1-year period. RESULTS: Patients demonstrated a variety of reasons for receiving a long-acting injectable antipsychotic drug, including insufficient control of symptoms, adverse events and convenience. After 1 year of treatment with long-acting risperidone, all patients showed improvements in their symptoms of schizophrenia over their original stable condition, and benefited from a considerable reduction or total disappearance of pre-existing extrapyramidal symptoms. Patients were more socially interactive, with no signs of sedation, fatigue, confusion, depression or anxiety, and none were considered to have relapsed or to require hospitalisation. Three of the four patients were considered to have had no signs of illness after 1 year, one of whom had returned to college and another to work. They demonstrate that patients can be switched from oral and depot medications without problems. There was little pain or discomfort and no inflammatory response experienced at the injection site. CONCLUSION: The cases demonstrate the suitability of long-acting risperidone in patients benefiting from long-term treatment and suggest its potential in all patients who are at risk of relapse.
Assuntos
Antipsicóticos/uso terapêutico , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adulto , Idoso , Química Farmacêutica , Preparações de Ação Retardada , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Risperidona/administração & dosagem , Psicologia do Esquizofrênico , Resultado do TratamentoRESUMO
The eukaryotic cell cycle is tightly regulated by the sequential activation and deactivation of the cyclin-dependent kinases (CDKs). Aberrant CDK activity is a common defect in human tumours, and clinically, it often confers a poor prognosis. The strong genetic link between CDKs and the molecular pathology of cancer has provided the rationale for developing small-molecule inhibitors of these kinases. X-ray crystallography recently has revealed the molecular details of CDK regulation by cyclin binding and phosphorylation, and by complex formation with endogenous inhibitors. Knowledge of the structure of CDK2 has been key in driving the design and development of a large number of ATP competitive inhibitors. Crystallography has revealed that the ATP-binding site of CDK2 can accommodate a number of diverse molecular frameworks, exploiting various sites of interaction. In addition, residues outside the main ATP-binding cleft have been identified that could be targeted to increase specificity and potency. These results suggest that it may be possible to design pharmacologically relevant ligands that act as specific and potent inhibitors of CDK activity. We provide a review of the current state of the field, along with an overview of our current inhibitor design studies.