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1.
Acta Crystallogr Sect E Struct Rep Online ; 70(Pt 10): o1118-9, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25484705

RESUMO

The title compound, C18H17BrO2, is a key inter-mediate in the synthesis of lomitapide mesylate, a microsomal triglyceride transfer protein inhibitor. Its asymmetric unit contains two independent mol-ecules with slightly different conformations; the mean planes of the 4-bromo-butyl and carboxyl-ate groups in the two mol-ecules form dihedral angles of 24.54 (12) and 17.10 (18)°. In the crystal, carboxyl-ate groups are involved in O-H⋯O hydrogen bonding, which leads to the formation of two crystallographically independent centrosymmetric dimers. Weak inter-molecular C-H⋯O inter-actions further link these dimers into layers parallel to the bc plane.

2.
Bioorg Med Chem Lett ; 24(4): 1108-10, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24456902

RESUMO

A series of novel pazopanib derivatives, 7a-m, were designed and synthesized by modification of terminal benzene and indazole rings in pazopanib. The structures of all the synthesized compounds were confirmed by (1)H NMR and MS. Their inhibitory activity against VEGFR-2, PDGFR-α and c-kit tyrosine kinases were evaluated. All the compounds exhibited definite kinase inhibition, in which compound 7l was most potent with IC50 values of 12 nM against VEGFR-2. Furthermore, compounds 7c, 7d and 7m demonstrated comparable inhibitory activity against three tyrosine kinases to pazopanib, and compound 7f showed superior inhibitory effects than that of pazopanib.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Pirimidinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Sulfonamidas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-kit/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
3.
Med Chem ; 10(3): 304-17, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24059684

RESUMO

Systematic mono-deoxylation of the four hydroxyl groups in the glucose moiety in dapagliflozin led to the discovery of 6-deoxydapagliflozin 1 as a more active sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor (IC50 = 0.67 nM against human SGLT2 (hSGLT2) vs 1.16 nM for dapagliflozin). It exhibited more potent blood glucose inhibitory activity in rat oral glucose tolerance test and induced more urinary glucose in rat urinary glucose excretion test than its parent compound dapagliflozin.


Assuntos
Compostos Benzidrílicos/farmacologia , Desoxiglucose/análogos & derivados , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/química , Glicemia/efeitos dos fármacos , Desoxiglucose/administração & dosagem , Desoxiglucose/química , Desoxiglucose/farmacologia , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Estrutura Molecular , Ratos , Transportador 2 de Glucose-Sódio , Relação Estrutura-Atividade
4.
Acta Crystallogr Sect E Struct Rep Online ; 68(Pt 5): o1291, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22590201

RESUMO

The mol-ecular skeleton of the title compound, C(9)H(11)N(3), is almost planar, with a maximum deviation of 0.0325 (19) Šfor the amino N atom. In the crystal, N-H⋯N hydrogen bonds establish the packing.

5.
Acta Crystallogr Sect E Struct Rep Online ; 67(Pt 12): o3139, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22199667

RESUMO

In the title compound, C(8)H(6)ClNO(4), the nitro and acet-oxy groups attached to the benzene ring at neighbouring positions are twisted from its plane by 29.4 (1) and 49.7 (1)°, respectively. In the crystal, weak C-H⋯O hydrogen bonds link mol-ecules into layers parallel to (101). The crystal packing exhibits short inter-molecular C⋯O distances of 2.925 (3) Å.

6.
Acta Crystallogr Sect E Struct Rep Online ; 67(Pt 7): o1787, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21837160

RESUMO

In the title mol-ecule, C(13)H(14)O(3)S(2), the thio-phene and benzene rings form a dihedral angle of 13.86 (13)°. In the crystal, weak inter-molecular C-H⋯O hydrogen bonds link the mol-ecules into layers parallel to the ab plane.

7.
Acta Crystallogr Sect E Struct Rep Online ; 67(Pt 6): o1546, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21754905

RESUMO

In the title compound, C(8)H(7)N(3)O(2), the mol-ecular skeleton is almost planar with a maximum deviation of 0.0484 (9) Šfor the methyl C atom. In the crystal, weak inter-molecular C-H⋯N and C-H⋯O hydrogen bonds help to establish the packing.

8.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 11): o2955, 2010 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-21589123

RESUMO

In the title compound, C(13)H(12)ClN(5), which is a derivative of the anti-tumor agent pazopanib {systematic name: 5-[[4-[(2,3-di-methyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzolsulfonamide}, the indazole and pyrim-idine fragments form a dihedral angle of 62.63 (5)°. In the crystal, pairs of mol-ecules related by twofold rotational symmetry are linked into dimers through π-π inter-actions between the indazole ring systems [centroid-centroid distance = 3.720 (2) Å]. Weak inter-molecular C-H⋯N hydrogen bonds further assemble these dimers into columns propagated in [001].

9.
Med Chem ; 3(6): 576-82, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18045208

RESUMO

A three dimensional Quantitative Structure Activity Relationship (3D-QSAR) model for a series of (S)-3-Aryl-5-substituted oxazolidinones was developed to gain insights into the design for potential new antibacterial agents. It was found that the Comparative Molecular Field Analysis (CoMFA) method yielded good results while the Comparative Molecular Similarity Indices Analysis (CoMSIA) was less satisfactory. The CoMFA method yielded a cross-validated correlation coefficient q(2) = 0.681, non-cross-validated R(2) = 0.991, SE (Standard Error ) = 0.054, and the value of statistical significance measure F = 266.98. The relative steric and electrostatic contributions are 0.542 and 0.458, respectively. These results indicate that the model possesses a high predictivity. Guided by this model, three new compounds were synthesized. All these compounds exhibit inhibitory activity; two of them were shown having high activity (MIC = 1.0 microg/ml). The activity observed by experiments was in good agreement with the theoretical one. It is anticipated that the present model would be of value in facilitating design of new potent antibacterial agents.


Assuntos
Antibacterianos/química , Desenho de Fármacos , Oxazolidinonas/química , Relação Quantitativa Estrutura-Atividade , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Oxazolidinonas/farmacologia , Eletricidade Estática
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