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2.
Bioorg Med Chem Lett ; 19(8): 2176-8, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19286380

RESUMO

A series of diphenyl ethers was prepared and evaluated for androgen receptor antagonist activity in human androgen receptor binding and cellular functional assays. Analogs with potent in vitro activities were evaluated for topical in vivo efficacy in the Golden Syrian Hamster ear model. Several compounds showed reduction in wax esters in this validated animal model.


Assuntos
Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/química , Antagonistas de Receptores de Andrógenos , Éteres Fenílicos/administração & dosagem , Éteres Fenílicos/síntese química , Sebo/efeitos dos fármacos , Sebo/metabolismo , Administração Tópica , Animais , Linhagem Celular Tumoral , Cricetinae , Humanos , Masculino , Mesocricetus , Receptores Androgênicos/química , Reprodutibilidade dos Testes
3.
Bioorg Med Chem Lett ; 19(5): 1310-3, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19201190

RESUMO

The first examples of thioether-substituted benzonitriles as potential soft-drug androgen receptor antagonists are reported. A number of 4-(alkylthio)- and of 4-(arylthio)-benzonitrile analogs were evaluated in human androgen receptor binding and cellular functional assays. Analogs with potent in vitro binding and cellular activities were evaluated for topical in vivo efficacy in the Golden Syrian hamster ear model. Analogs from both the 4-(alkylthio)- and of 4-(arylthio)-benzonitrile series showed moderate reduction of wax esters in vivo.


Assuntos
Antagonistas de Androgênios/química , Antagonistas de Receptores de Andrógenos , Nitrilas/síntese química , Nitrilas/farmacologia , Sebo/efeitos dos fármacos , Sebo/metabolismo , Antagonistas de Androgênios/farmacologia , Animais , Linhagem Celular , Cricetinae , Humanos , Insetos , Masculino , Mesocricetus , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Receptores Androgênicos/metabolismo
4.
Int J Pharm ; 367(1-2): 37-43, 2009 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-18929636

RESUMO

To understand drug delivery to the sebum filled hair and sebaceous follicles, it is essential to use an artificial sebum as a surrogate of the human sebum for the investigation of drug transport properties. Artificial sebum L was developed in-house based on the chemical similarity to human sebum. The partition and diffusion of model compounds (ethyl 4-hydroxybenzoate, butyl 4-hydroxybenzoate, and hexyl 4-hydroxybenzoate) were measured in human sebum, hamster ear and body sebum (a commonly used animal model), and four representative artificial sebum samples (N, S, F, and L) in which artificial sebums, N, S and F were selected based on the available literature. DSC and NMR studies were also conducted on all sebums to compare their melting properties and chemical compositions. In vitro studies show that the partition coefficients of the three model compounds in artificial sebum L were similar to that of human sebum, whereas the hamster ear and body sebum, and other three artificial sebum samples were different from that of human sebum. Additionally, the in vitro sebum flux (microg/(cm(2)min) of three model compounds through artificial sebum L was closer to that of human sebum when compared with the other three artificial sebum (N, S and F), hamster body and hamster ear sebum. The results of this study indicate that the artificial sebum L could be used as an alternative to human sebum, as the physicochemical properties of this artificial sebum is relatively similar to human sebum.


Assuntos
Modelos Biológicos , Sebo/química , Administração Cutânea , Animais , Transporte Biológico , Varredura Diferencial de Calorimetria , Cromatografia Líquida de Alta Pressão , Cricetinae , Sistemas de Liberação de Medicamentos , Folículo Piloso/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Sebo/metabolismo , Especificidade da Espécie
5.
J Med Chem ; 51(21): 7010-4, 2008 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-18921992

RESUMO

4-((1 R,2 R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)- 6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (-)- 6a was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.


Assuntos
Antagonistas de Receptores de Andrógenos , Cicloexanóis/síntese química , Cicloexanóis/farmacologia , Nitrilas/síntese química , Nitrilas/farmacologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Pele , Cristalografia por Raios X , Cicloexanóis/química , Desenho de Fármacos , Ligantes , Modelos Moleculares , Estrutura Molecular , Nitrilas/química , Fármacos Fotossensibilizantes/química , Receptores Androgênicos/química , Receptores Androgênicos/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Esteroides/química , Relação Estrutura-Atividade
6.
J Lipid Res ; 49(3): 686-92, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18094397

RESUMO

A NMR spectroscopic method is described that enables the quantitation of specific lipid classes and components, independent of fatty acid composition. We demonstrate this method for measuring cholesterol, squalene, and pools of sterol esters, wax esters (WEs), and triglyceride (TG) components in sebum and meibum. When 600 MHz NMR equipment is used in conjunction with highly sensitive cryogenically cooled probes, this method has adequate sensitivity, and for some applications, advantages over commonly used HPLC-evaporative light-scattering detection and mass spectrometry-based approaches. This method is shown to be useful for preclinical and clinical monitoring of the efficacy of sebum-reducing agents in animals and humans. In Syrian hamsters, 3% topical flutamide and 20 mg/kg oral isotretinoin reduced sterol esters by 18.7% and 30.0%, respectively, and reduced WEs by 32.9% and 31.8%, respectively, as measured in a punch biopsy of the ear. In a 72 patient clinical methodology study, the assay delivered reproducible and noninvasive measurements of WEs, cholesteryl esters, TGs, and squalene from Sebutape skin blots. The quantitative results of sebum analysis obtained by the NMR method correlate well with those obtained with HPLC-based approaches. This approach may be broadly applicable to cases in which fatty acid-independent quantification of lipid classes is desired.


Assuntos
Lipídeos/análise , Espectroscopia de Ressonância Magnética/métodos , Sebo/química , Animais , Cricetinae , Humanos , Mesocricetus , Métodos
7.
Bioorg Med Chem Lett ; 17(20): 5693-7, 2007 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17766112

RESUMO

A series of amino-pyridines were synthesized and evaluated for androgen antagonist activities. Among these compounds, (R)-(+)-6-[methyl-(1-phenyl-ethyl)-amino]-4-trifluoromethyl-nicotinonitrile was the most active example of this class. This compound displayed potent androgen receptor antagonist activity as well as favorable pharmacokinetic characteristics for a potential topical agent. It also demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.


Assuntos
Aminopiridinas/química , Aminopiridinas/farmacologia , Antagonistas de Receptores de Andrógenos , Cabelo/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Sebo/efeitos dos fármacos , Sebo/metabolismo , Aminopiridinas/síntese química , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C3H , Modelos Moleculares , Estrutura Molecular , Receptores Androgênicos/metabolismo , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 17(20): 5529-32, 2007 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17764935

RESUMO

A series of substituted 4-aryl-2-trifluoromethylbenzonitrile analogs were evaluated in the human androgen receptor binding and cellular functional assays. Analogs with sufficient in vitro binding and cellular potency (IC(50)<200 nM) were tested in the progesterone receptor binding assay for selectivity and in the Golden Syrian hamster ear model for in vivo efficacy. Within the series, compound 4 e was identified to be the most active analog in vivo (wax ester inhibition=86%).


Assuntos
Antagonistas de Receptores de Andrógenos , Flúor/química , Nitrilas/química , Nitrilas/farmacologia , Receptores Androgênicos/metabolismo , Sebo/efeitos dos fármacos , Sebo/metabolismo , Humanos , Concentração Inibidora 50 , Metilação , Estrutura Molecular , Nitrilas/síntese química , Relação Estrutura-Atividade
9.
J Chromatogr B Analyt Technol Biomed Life Sci ; 826(1-2): 31-40, 2005 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-16139575

RESUMO

A novel skin tissue extraction method coupled with liquid chromatography-tandem mass spectrometry (LC/MS/MS) detection was developed and validated for the analysis of endogenous pyrrole-2,3,5-tricarboxylic acid (PTCA), a eumelanin specific biomarker, in human skin punch biopsies. The analyte is extracted from the matrix (2 mm skin punch biopsies) using a simple oxidative degradation procedure. The extract supernatants are evaporated, reconstituted in mobile phase solvent, and injected into the LC/MS/MS system without further derivatization. The chromatographic separation is achieved on a reverse phase high performance liquid chromatography (HPLC) column. The accuracy and precision of the method was determined over the concentration range of 1-1000 ng/mL PTCA from human skin extracts in three validation batch runs. Inter-assay precision (%CV) and accuracy (%R.E.) of the quality control samples were

Assuntos
Biomarcadores/análise , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Melaninas/análise , Pirróis/análise , Pele/química , Negro ou Afro-Americano , Animais , Biópsia/métodos , Humanos , Camundongos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Pigmentação da Pele , População Branca
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