RESUMO
The synthesis and structure-activity relationships of a novel aryl uracil series which contains a fused 5,6-bicyclic ring unit for HCV NS5B inhibition is described. Several analogs display replicon cell culture potencies in the low nanomolar range along with excellent rat pharmacokinetic values.
Assuntos
Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Uracila/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacocinética , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Hepacivirus/enzimologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/metabolismo , Ratos , Relação Estrutura-Atividade , Uracila/farmacologia , Proteínas não Estruturais Virais/metabolismoRESUMO
Pharmacological targeting of the dopamine D4 receptor (D4R)âexpressed in brain regions that control cognition, attention, and decision-makingâcould be useful for several neuropsychiatric disorders including substance use disorders (SUDs). This study focused on the synthesis and evaluation of a novel series of benzothiazole analogues designed to target D4R. We identified several compounds with high D4R binding affinity (Ki ≤ 6.9 nM) and >91-fold selectivity over other D2-like receptors (D2R, D3R) with diverse partial agonist and antagonist profiles. Novel analogue 16f is a potent low-efficacy D4R partial agonist, metabolically stable in rat and human liver microsomes, and has excellent brain penetration in rats (AUCbrain/plasma > 3). 16f (5-30 mg/kg, i.p.) dose-dependently decreased iv cocaine self-administration in rats, consistent with previous results produced by D4R-selective antagonists. Off-target antagonism of 5-HT2A or 5-HT2B may also contribute to these effects. Results with 16f support further efforts to target D4R in SUD treatment.
Assuntos
Cocaína , Transtornos Relacionados ao Uso de Substâncias , Humanos , Animais , Ratos , Serotonina , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Encéfalo , Cocaína/farmacologiaRESUMO
The design and synthesis of indazolinone containing kinase inhibitors are reported. Regioisomers that showed profound potency variation in previously-reported isoindolinone and aminoindazole systems were surprisingly found to have similar potencies in the case of the indazolinone chemical series. An interpretation using differential hinge hydrogen bonding and tautomeric equilibrium of indazolinone ring system is supported by quantum mechanics calculations. The equipotent inhibition of a representative kinase (KDR) by regioisomeric indazolinones 4 and 5 is clear evidence that in case of the indazolinone hinge, both tautomers are equally favored, and should be considered in design of inhibitors.
Assuntos
Indazóis/síntese química , Inibidores de Proteínas Quinases/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Indazóis/farmacologia , Isomerismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
A high throughput screening (HTS) hit, 1 (Plk1 K(i)=2.2 µM) was optimized and evaluated for the enzymatic inhibition of Plk-1 kinase. Molecular modeling suggested the importance of adding a hydrophobic aromatic amine side chain in order to improve the potency by a classic kinase H-donor-acceptor binding mode. Extensive SAR studies led to the discovery of 49 (Plk1 K(i)=5 nM; EC(50)=1.05 µM), which demonstrated moderate efficacy at 100 mpk in a MiaPaCa tumor model, with no overt toxicity.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Neoplasias Experimentais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Quinase 1 Polo-LikeRESUMO
Four hinge-binding scaffolds have been explored for novel selective Aurora kinase inhibitors. The structure activity relationship, selectivity and pharmacokinetic profiles have been evaluated.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Aurora Quinases , Linhagem Celular , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.
Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/química , Pirimidinas/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Aminação , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinase B , Aurora Quinases , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Estrutura Molecular , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In an effort to identify multi-targeted kinase inhibitors with a novel spectrum of kinase activity, a screen of Abbott proprietary KDR inhibitors against a broad panel of kinases was conducted and revealed a series of thienopyridine ureas with promising activity against the Aurora kinases. Modification of the diphenyl urea and C7 moiety of these compounds provided potent inhibitors with good pharmacokinetic profiles that were efficacious in mouse tumor models after oral dosing. Compound 2 (ABT-348) of this series is currently undergoing Phase I clinical trials in solid and hematological cancer populations.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Ureia/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Humanos , Camundongos , Inibidores de Proteínas Quinases/química , Fator A de Crescimento do Endotélio VascularRESUMO
In an effort to discover Aurora kinase inhibitors, an HTS hit revealed an amide containing pyrrolopyrimidine compound. Replacement of the pyrrolopyrimidine residue with a thienopyrimidine moiety led to a series of potent and selective Aurora inhibitors.
Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Aurora Quinases , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Ligação de Hidrogênio , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of quinoline derivatives was synthesized as potential bioisosteric replacements for the benzothiadiazine moiety of earlier Hepatitis C NS5B polymerase inhibitors. Several of these compounds exhibited potent activity in enzymatic and replicon assays.
Assuntos
Benzotiadiazinas/farmacologia , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Benzotiadiazinas/química , Hepacivirus/enzimologia , Hepacivirus/fisiologia , Inibidores de Proteases/química , Replicação ViralRESUMO
The ectodomain of HIV-1 gp41 mediates the fusion of viral and host cellular membranes. The peptide-based drug Enfuvirtide(1) is precedent that antagonists of this fusion activity may act as anti HIV-agents. Here, NMR screening was used to discover non-peptide leads against this target and resulted in the discovery of a new benzamide 1 series. This series is non-peptide, low molecular weight, and analogs have activity in a cell fusion assay with EC50 values ranging 3-41microM. Structural work on the gp41/benzamide 1 complex was determined by NMR spectroscopy using a designed model peptide system that mimics an open pocket of the fusogenic form of the protein.
Assuntos
Fármacos Anti-HIV/química , Benzamidas/química , Proteína gp41 do Envelope de HIV/química , Inibidores da Fusão de HIV/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Cristalografia por Raios X , Enfuvirtida , Proteína gp41 do Envelope de HIV/metabolismo , Proteína gp41 do Envelope de HIV/farmacologia , Inibidores da Fusão de HIV/síntese química , Inibidores da Fusão de HIV/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The design and enzyme activities of a novel class of imidazo[2,1-b]thiazoles is presented.
Assuntos
Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Tiazóis/farmacologia , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
A series of benzoisoxazoles and benzoisothiazoles have been synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs). Structure-activity relationship studies led to the identification of 3-amino benzo[ d]isoxazoles, incorporating a N, N'-diphenyl urea moiety at the 4-position that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor families of RTKs. Within this series, orally bioavailable compounds possessing promising pharmacokinetic profiles were identified, and a number of compounds demonstrated in vivo efficacy in models of VEGF-stimulated vascular permeability and tumor growth. In particular, compound 50 exhibited an ED 50 of 2.0 mg/kg in the VEGF-stimulated uterine edema model and 81% inhibition in the human fibrosarcoma (HT1080) tumor growth model when given orally at a dose of 10 mg/kg/day.
Assuntos
Isoxazóis/síntese química , Modelos Moleculares , Oxazóis/síntese química , Compostos de Fenilureia/síntese química , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Sítios de Ligação , Disponibilidade Biológica , Permeabilidade Capilar/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Edema/tratamento farmacológico , Feminino , Humanos , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Oxazóis/farmacocinética , Oxazóis/farmacologia , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Fosforilação , Relação Estrutura-Atividade , Útero/irrigação sanguínea , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of isoxazolo[3,4-b]quinoline-3,4(1H,9H)-diones were synthesized as potent inhibitors against Pim-1 and Pim-2 kinases. The structure-activity-relationship studies started from a high-throughput screening hit and was guided by molecular modeling of inhibitors in the active site of Pim-1 kinase. Installing a hydroxyl group on the benzene ring of the core has the potential to form a key hydrogen bond interaction to the hinge region of the binding pocket and thus resulted in the most potent inhibitor, 19, with K(i) values at 2.5 and 43.5 nM against Pim-1 and Pim-2, respectively. Compound 19 also exhibited an activity profile with a high degree of kinase selectivity.
Assuntos
Isoxazóis/síntese química , Isoxazóis/farmacologia , Modelos Moleculares , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Quinolinas/síntese química , Quinolinas/farmacologia , Técnicas de Química Combinatória , Cristalografia por Raios X , Humanos , Isoxazóis/química , Conformação Molecular , Estrutura Molecular , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
We report the discovery of the pyrimido-diazepine scaffolds as novel adenine mimics. Structure-based design led to the discovery of analogs with potent inhibitory activity against receptor tyrosine kinases, such as KDR, Flt3 and c-Kit. Compound 14 exhibited low nanomolar KDR enzymatic and cellular potencies (IC(50)=9 and 52 nM, respectively).
Assuntos
Azepinas/síntese química , Azepinas/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Células 3T3 , Animais , Azepinas/química , Ligação de Hidrogênio , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina Quinases/química , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
4,4-Dialkyl-1-hydroxy-3-oxo-3.4-dihydronaphthalene-3-yl benzothiadiazine derivatives were synthesized and evaluated as inhibitors of genotypes 1a and 1b HCV NS5B polymerase. A number of these compounds exhibited potent activity against genotypes 1a and 1b HCV polymerase in both enzymatic and cell culture activities. A representative compound also showed favorable pharmacokinetics in the rat.
Assuntos
Antivirais/síntese química , Antivirais/farmacocinética , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Área Sob a Curva , Química Farmacêutica/métodos , Desenho de Fármacos , Genótipo , Infusões Intravenosas , Concentração Inibidora 50 , Modelos Químicos , Ratos , Proteínas não Estruturais Virais/genéticaRESUMO
Tumor angiogenesis is mediated by KDR and other VEGFR and PDGFR kinases. Their inhibition presents an attractive approach for developing anticancer therapeutics. Here, we report a series of aminopyrazolopyridine ureas as potent VEGFR/PDGFR multitargeted kinase inhibitors. A number of compounds have been identified to be orally bioavailable and efficacious in the mouse edema model.
Assuntos
Aminopiridinas/química , Aminopiridinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ureia/análogos & derivados , Administração Oral , Aminopiridinas/síntese química , Aminopiridinas/farmacocinética , Animais , Disponibilidade Biológica , Edema/tratamento farmacológico , Edema/metabolismo , Feminino , Concentração Inibidora 50 , Camundongos , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/farmacologia , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/farmacologia , Doenças Uterinas/tratamento farmacológico , Doenças Uterinas/metabolismoRESUMO
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.
Assuntos
Citosina/análogos & derivados , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Hepacivirus/enzimologia , Estilbenos/química , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Técnicas de Química Sintética , Citosina/síntese química , Citosina/química , Citosina/farmacocinética , Citosina/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Permeabilidade , Estereoisomerismo , Sulfonamidas/química , Sulfonamidas/farmacocinética , Distribuição Tecidual , Proteínas não Estruturais Virais/químicaRESUMO
Based on the crystallographic analysis of a urea-checkpoint kinase 1 (Chk1) complex and molecular modeling, a class of macrocyclic Chk1 inhibitors were designed and their biological activities were evaluated. An efficient synthetic methodology for macrocyclic ureas was developed with Grubbs metathesis macrocyclization as the key step. The structure-activity relationship studies demonstrated that the macrocyclization retains full Chk1 inhibition activity and that the 4-position of the phenyl ring can tolerate a wide variety of substituents. These novel Chk1 inhibitors exhibit excellent selectivity over a panel of more than 70 kinases. Compounds 5b, 5c, 5f, 15, 16d, 17g, 17h, 17k, 18d, and 22 were identified as ideal Chk1 inhibitors, which showed little or no single-agent activity but significantly potentiate the cytotoxicities of the DNA-damaging antitumor agents doxorubicin and camptothecin. These novel Chk1 inhibitors abrogate the doxorubicin-induced G2 and camptothecin-induced S checkpoint arrests, confirming that their potent biological activities are mechanism-based through Chk1 inhibition.
Assuntos
Antineoplásicos/síntese química , Compostos Macrocíclicos/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/química , Ureia/análogos & derivados , Ureia/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Camptotecina/farmacologia , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Cristalografia por Raios X , Dano ao DNA , Doxorrubicina/farmacologia , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Relação Estrutura-Atividade , Ureia/química , Ureia/farmacologiaRESUMO
Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment of type 2 diabetes. They exert their beneficial effects by increasing the levels of active glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are two important incretins for glucose homeostasis. Starting from a high-throughput screening hit, we were able to identify a series of piperidinone- and piperidine-constrained phenethylamines as novel DPP4 inhibitors. Optimized compounds are potent, selective, and have good pharmacokinetic profiles.
Assuntos
Inibidores de Adenosina Desaminase , Inibidores da Dipeptidil Peptidase IV , Glicoproteínas/antagonistas & inibidores , Fenetilaminas/síntese química , Piperidinas/síntese química , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Dipeptidil Peptidase 4 , Humanos , Conformação Molecular , Fenetilaminas/farmacocinética , Fenetilaminas/farmacologia , Piperidinas/farmacocinética , Piperidinas/farmacologia , Piperidonas/síntese química , Piperidonas/farmacocinética , Piperidonas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited a strong ability to abrogate G2 arrest and increased the cytotoxicity of camptothecin by 19-fold against SW620 cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two important binding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, were hydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bond between the methoxy group and Lys38 of the protein.