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1.
J Med Chem ; 61(17): 7503-7524, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30080045

RESUMO

The glycine transporter 1 (GlyT1) has emerged as a key novel target for the treatment of schizophrenia. Herein, we report the synthesis and biological evaluation of aminotetralines and aminochromanes as novel classes of competitive GlyT1 inhibitors. Starting from a high-throughput screening hit, structure-activity relationship studies led first to the discovery of aminotetralines displaying high GlyT1 potency and selectivity, with favorable pharmacokinetic properties. Systematic investigations of various parameters (e.g., topological polar surface area, number of hydrogen bond donors) guided by ex vivo target occupancy evaluation resulted in lead compounds possessing favorable brain penetration properties as for (7 S,8 R)-27a. Further optimization revealed compounds with reduced efflux liabilities as for aminochromane 51b. In an in vivo efficacy model (7 S,8 R)-27a, dose-dependently reversed L-687,414 induced hyperlocomotion in mice with an ED50 of 0.8 mg/kg. All these results suggest (7 S,8 R)-27a and 51b as new GlyT1 inhibitors worthy of further profiling.


Assuntos
Encéfalo/efeitos dos fármacos , Cromanos/química , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Tetra-Hidronaftalenos/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Ligação Competitiva , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Feminino , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Ensaios de Triagem em Larga Escala/métodos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Pirrolidinonas/efeitos adversos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xenopus
2.
Bioorg Med Chem Lett ; 20(11): 3291-4, 2010 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-20457518

RESUMO

The synthesis and SAR of a series of indazole TRPV1 antagonists leading to the discovery of 21 (ABT-116) is described. Biological studies demonstrated potent in vitro and in vivo activity for 21, as well as suitable physicochemical and pharmacokinetic properties for advancement to clinical development for pain management.


Assuntos
Analgésicos/farmacologia , Indazóis/farmacologia , Compostos de Fenilureia/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Analgésicos/farmacocinética , Animais , Humanos , Indazóis/farmacocinética , Compostos de Fenilureia/farmacocinética , Ratos , Relação Estrutura-Atividade
3.
J Med Chem ; 51(3): 392-5, 2008 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-18183945

RESUMO

Vanilloid receptor TRPV1 is a cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation by several pharmaceutical companies in an effort to identify novel agents for pain management. Here we report that replacement of substituted benzyl groups by an indan rigid moiety in a previously described N-indazole- N'-benzyl urea series led to a number of TRPV1 antagonists with significantly increased in vitro potency and enhanced drug-like properties. Extensive evaluation of pharmacological, pharmacokinetic, and toxicological properties of synthesized analogs resulted in identification of ( R)-7 ( ABT-102). Both the analgesic activity and drug-like properties of ( R)-7 support its advancement into clinical pain trials.


Assuntos
Analgésicos/síntese química , Indazóis/síntese química , Indenos/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Administração Oral , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Cães , Haplorrinos , Humanos , Técnicas In Vitro , Indazóis/farmacocinética , Indazóis/farmacologia , Indenos/farmacocinética , Indenos/farmacologia , Microssomos Hepáticos/metabolismo , Dor/tratamento farmacológico , Dor/etiologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/farmacocinética , Ureia/farmacologia
4.
J Med Chem ; 48(3): 744-52, 2005 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-15689158

RESUMO

Novel transient receptor potential vanilloid 1 (TRPV1) receptor antagonists with various bicyclic heteroaromatic pharmacophores were synthesized, and their in vitro activity in blocking capsaicin activation of TRPV1 was assessed. On the basis of the contribution of these pharmacophores to the in vitro potency, they were ranked in the order of 5-isoquinoline > 8-quinoline = 8-quinazoline > 8-isoquinoline > or = cinnoline approximately phthalazine approximately quinoxaline approximately 5-quinoline. The 5-isoquinoline-containing compound 14a (hTRPV1 IC50 = 4 nM) exhibited 46% oral bioavailability and in vivo activity in animal models of visceral and inflammatory pain. Pharmacokinetic and pharmacological properties of 14a are substantial improvements over the profile of the high-throughput screening hit 1 (hTRPV1 IC50 = 22 nM), which was not efficacious in animal pain models and was not orally bioavailable.


Assuntos
Analgésicos/síntese química , Isoquinolinas/síntese química , Dor/tratamento farmacológico , Receptores de Droga/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Dor Abdominal/tratamento farmacológico , Administração Oral , Analgésicos/química , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Cálcio/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Hiperalgesia/tratamento farmacológico , Isoquinolinas/química , Isoquinolinas/farmacologia , Modelos Moleculares , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/farmacologia , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia , Ratos , Eletricidade Estática , Relação Estrutura-Atividade , Ureia/química , Ureia/farmacologia
5.
J Med Chem ; 45(8): 1697-711, 2002 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-11931625

RESUMO

The synthesis and structure-activity relationship study of a series of compounds with heterocycles in place of the cis double bond in combretastatin A-4 (CA-4) are described. Substituted tosylmethyl isocyanides were found to be the key intermediates in construction of the heterocycles. Cytotoxicities of the heterocycle-based CA-4 analogues were evaluated against NCI-H460 and HCT-15 cancer cell lines. 3-Amino-4-methoxyphenyl and N-methyl-indol-5-yl were the best replacements for the 3-hydroxy-4-methoxyphenyl in CA-4. 4,5-Disubstituted imidazole was found to be the best for the replacement of the cis double bond in CA-4. Medicinal chemistry efforts led to the discovery of compounds 24h and 25f that were found to be 32 and 82% bioavailable, respectively, in rat. Evaluation of 24h and 25f against murine M5076 reticulum sarcoma in mice revealed that both compounds were orally efficacious with an increase in life span of 38.5 and 40.5%, respectively.


Assuntos
Antineoplásicos/síntese química , Imidazóis/síntese química , Estilbenos/química , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Biopolímeros , Divisão Celular/efeitos dos fármacos , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Haplorrinos , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Nus , Transplante de Neoplasias , Ratos , Relação Estrutura-Atividade , Transplante Heterólogo , Tubulina (Proteína)/química , Células Tumorais Cultivadas
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