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1.
Clin Exp Pharmacol Physiol ; 37(5-6): 636-40, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20132238

RESUMO

1. It has been shown that tubulin-binding agents can destabilize cellular microtubules and suppress tumour growth; but it has also become apparent that some compounds can exert anti-vascular effects within the neovasculature of a solid tumour. To date, the difficulty with these targets has been the ability to selectivity induce vascular damage to the tumour while leaving normal vasculature unaffected. The data presented here characterizes the in vivo, tumour selective, anti-vascular effects of the novel tubulin-binding agent A-318315. 2. To that purpose, we have used an anaesthetized in vivo rat model designed to quantify acute changes in regional vascular resistance (VR) in both tumour and non-tumour vascular beds, simultaneously. Tissue-isolated tumours (approximately 1.25 gm) with blood flow supplied by a single epigastric artery were grown in the hindlimb of adult male rats. Blood flow to the tumour, mesenteric, renal and normal (non-tumour epigastric) arteries was measured pre-dose and post-dose under anaesthesia. 3. A-318315 was tested at 3, 10 and 30 mg/kg, i.v. These doses produced modest, transient increases in mean arterial pressure with little to no effect on heart rate. At peak effect, tumour VR increased to 175 +/- 47, 337 +/- 77 and 751 +/- 151% above the baseline, for the 3, 10 and 30 mg/kg doses, respectively, whereas VR was only modestly and transiently increased in normal epigastric (88 +/- 19%), mesenteric (33 +/- 3.3%) and renal arteries (17 +/- 8.6%). 4. These data demonstrate that A-318315 produces marked reductions in tumour blood flow in the rat at doses that exert minor effects on normal vascular function.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antimitóticos/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Indóis/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Sulfonamidas/uso terapêutico , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/farmacologia , Animais , Antimitóticos/efeitos adversos , Antimitóticos/farmacocinética , Antimitóticos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Indóis/efeitos adversos , Indóis/farmacocinética , Indóis/farmacologia , Masculino , Estrutura Molecular , Neovascularização Patológica/metabolismo , Neovascularização Patológica/fisiopatologia , Ratos , Ratos Endogâmicos F344 , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Tubulina (Proteína)/metabolismo , Resistência Vascular/efeitos dos fármacos
2.
Clin Cancer Res ; 13(9): 2728-37, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17473206

RESUMO

PURPOSE: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888. EXPERIMENTAL DESIGN: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation. RESULTS: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K(i)s of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d x 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity. CONCLUSIONS: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.


Assuntos
Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases , Administração Oral , Animais , Antineoplásicos Alquilantes/uso terapêutico , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Dano ao DNA , Modelos Animais de Doenças , Cães , Sinergismo Farmacológico , Feminino , Haplorrinos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Endogâmicos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Med Chem ; 50(7): 1584-97, 2007 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-17343372

RESUMO

In our continued efforts to search for potent and novel receptor tyrosine kinase (RTK) inhibitors as potential anticancer agents, we discovered, through a structure-based design, that 3-aminoindazole could serve as an efficient hinge-binding template for kinase inhibitors. By incorporating an N,N'-diaryl urea moiety at the C4-position of 3-aminodazole, a series of RTK inhibitors were generated, which potently inhibited the tyrosine kinase activity of the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor families. A number of compounds with potent oral activity were identified by utilizing an estradiol-induced mouse uterine edema model and an HT1080 human fibrosarcoma xenograft tumor model. In particular, compound 17p (ABT-869) was found to possess favorable pharmacokinetic profiles across different species and display significant tumor growth inhibition in multiple preclinical animal models.


Assuntos
Inibidores da Angiogênese/síntese química , Indazóis/síntese química , Compostos de Fenilureia/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Trifosfato de Adenosina/química , Administração Oral , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Sítios de Ligação , Edema/induzido quimicamente , Edema/patologia , Estradiol , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indazóis/química , Indazóis/farmacologia , Masculino , Camundongos , Modelos Moleculares , Células NIH 3T3 , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Fosforilação , Receptores Proteína Tirosina Quinases/química , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Útero/efeitos dos fármacos , Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Bioorg Med Chem Lett ; 16(6): 1679-85, 2006 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-16403626

RESUMO

A novel series of Akt/PKB inhibitors derived from a screening lead (1) has been prepared. The novel trans-3,4'-bispyridinylethylenes described herein are potent inhibitors of Akt/PKB with IC(50) values in the low double-digit nanomolar range against Akt1. Compound 2q shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to modest selectivity against closely related kinases in the AGC and CMGC families. The cellular activities including inhibition of cell growth and phosphorylation of downstream target GSK3 are also described. The X-ray structure of compound 2q complexed with PKA in the ATP binding site was determined.


Assuntos
Antineoplásicos , Inibidores Enzimáticos , Etilenos , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sítios de Ligação , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Etilenos/síntese química , Etilenos/farmacologia , Quinase 3 da Glicogênio Sintase , Humanos , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases/antagonistas & inibidores , Relação Estrutura-Atividade
5.
J Med Chem ; 48(19): 6066-83, 2005 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-16162008

RESUMO

A series of novel thienopyrimidine-based receptor tyrosine kinase inhibitors has been discovered. Investigation of structure-activity relationships at the 5- and 6-positions of the thienopyrimidine nucleus led to a series of N,N'-diaryl ureas that potently inhibit all of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinases. A kinase insert domain-containing receptor (KDR) homology model suggests that these compounds bind to the "inactive conformation" of the enzyme with the urea portion extending into the back hydrophobic pocket adjacent to the adenosine 5'-triphosphate (ATP) binding site. A number of compounds have been identified as displaying excellent in vivo potency. In particular, compounds 28 and 76 possess favorable pharmacokinetic (PK) profiles and demonstrate potent antitumor efficacy against the HT1080 human fibrosarcoma xenograft tumor growth model (tumor growth inhibition (TGI) = 75% at 25 mg/kg.day, per os (po)).


Assuntos
Antineoplásicos/síntese química , Pirimidinas/síntese química , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Trifosfato de Adenosina/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Edema/induzido quimicamente , Edema/patologia , Estradiol , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Modelos Moleculares , Células NIH 3T3 , Fosforilação , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Ureia/química , Ureia/farmacologia , Útero/efeitos dos fármacos , Útero/patologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Bioorg Med Chem Lett ; 14(18): 4603-6, 2004 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-15324873

RESUMO

Two novel series of potent and selective FTase inhibitors have been synthesized using structure-based design. Medicinal chemistry efforts led to the discovery of compound 4e with potent cellular activity and good oral bioavailability in dog. A synthetic route toward novel heterocycles 1,5-dimethyl-6-oxo-4-aryl-1,6-dihydro-pyridine-2-carbonitrile was established. The structure of compound 5c was confirmed by X-ray crystallography.


Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Piridinas/síntese química , Administração Oral , Alquil e Aril Transferases/química , Animais , Cristalografia por Raios X , Cães , Farnesiltranstransferase , Piridinas/química , Relação Estrutura-Atividade
7.
Cancer Chemother Pharmacol ; 54(3): 273-81, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15173957

RESUMO

Selective induction of vascular damage within a growing tumor is a potentially important approach in the search for potent anticancer therapeutics. Tubulin-binding (antimitotic) agents destabilize cellular microtubules, suppress tumor growth, and exert antivascular effects with varying degrees of tumor selectivity in preclinical models. The tumor-selective, antivascular effects of ABT-751, a novel, orally active antimitotic agent, currently in phase II clinical development, were characterized in vivo in the present study. We developed an in vivo rat model designed to quantify acute changes in regional vascular resistance (VR) in both tumor and non-tumor vascular beds simultaneously. Tissue-isolated tumors (1 g) with blood flow supplied by a single epigastric artery were grown in rats. Subsequently, tumor blood flow was measured under anesthesia in solid tumors and also in mesenteric, renal, and normal epigastric arteries. Phenylephrine-induced (1 micromol/kg) increases in VR were not different between tumor and non-tumor epigastric arteries, suggesting that tumor vessels possess relatively normal vasoconstrictive function. ABT-751 (3, 10, and 30 mg/kg; i.v.) produced modest transient increases in mean arterial pressure with no effect on heart rate. Tumor VR increased to 75+/-36, 732+/-172, and 727+/-125% above baseline, respectively (P<0.05 for the 10 and 30 mg/kg doses), whereas VR in normal epigastric arteries was not significantly affected. Administration of ABT-751 produced transient modest ( P<0.05) increases in mesenteric VR and no effect on renal VR. These results demonstrate that ABT-751 produces marked reductions in tumor blood flow in the intact rat at doses that exert negligible effects on normal vascular function.


Assuntos
Neoplasias Abdominais/irrigação sanguínea , Antineoplásicos/farmacologia , Glioma/irrigação sanguínea , Sulfonamidas/farmacologia , Resistência Vascular/efeitos dos fármacos , Neoplasias Abdominais/veterinária , Administração Oral , Animais , Modelos Animais de Doenças , Glioma/veterinária , Hemodinâmica/efeitos dos fármacos , Masculino , Neoplasias Experimentais/irrigação sanguínea , Piridonas , Ratos , Ratos Endogâmicos F344 , Tubulina (Proteína)/metabolismo
8.
J Med Chem ; 47(3): 612-26, 2004 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-14736242

RESUMO

A novel series of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles have been synthesized as selective farnesyltransferase inhibitors using structure-based design. X-ray cocrystal structures of compound 20-FTase-HFP and A313326-FTase-HFP confirmed our initial design. The decreased interaction between the aryl groups and Ser 48 in GGTase-I binding site could be one possible reason to explain the improved selectivity for this new series of FTase inhibitors. Medicinal chemistry efforts led to the discovery of compound 64 with potent cellular activity (EC(50) = 3.5 nM) and outstanding pharmacokinetic profiles in dog (96% bioavailable, 18.4 h oral t(1/2), and 0.19 L/(h x kg) plasma clearance).


Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Benzamidas/síntese química , Imidazóis/síntese química , Nitrilas/síntese química , Administração Oral , Alquil e Aril Transferases/química , Alquil e Aril Transferases/metabolismo , Animais , Benzamidas/farmacocinética , Benzamidas/farmacologia , Disponibilidade Biológica , Permeabilidade da Membrana Celular , Cristalografia por Raios X , Cães , Desenho de Fármacos , Farnesiltranstransferase , Imidazóis/farmacocinética , Imidazóis/farmacologia , Modelos Moleculares , Estrutura Molecular , Nitrilas/farmacocinética , Nitrilas/farmacologia , Relação Estrutura-Atividade
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