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1.
Bioorg Med Chem Lett ; 26(2): 466-471, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26687487

RESUMO

Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders.


Assuntos
Oxidiazóis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Tiadiazóis/farmacologia , Animais , Encéfalo/metabolismo , Ácido Glutâmico/metabolismo , Células Hep G2 , Humanos , Ligação de Hidrogênio , Cinética , Oxidiazóis/sangue , Oxidiazóis/síntese química , Ratos , Solubilidade , Relação Estrutura-Atividade , Tiadiazóis/sangue , Tiadiazóis/síntese química
2.
Bioorg Med Chem Lett ; 25(3): 581-6, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25556092

RESUMO

Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.


Assuntos
Isoxazóis/química , Prolina/química , Ácido Pirrolidonocarboxílico/análogos & derivados , Receptor CB2 de Canabinoide/agonistas , Animais , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/tratamento farmacológico , Meia-Vida , Humanos , Isoxazóis/farmacocinética , Isoxazóis/uso terapêutico , Ligantes , Masculino , Microssomos Hepáticos/metabolismo , Prolina/farmacocinética , Prolina/uso terapêutico , Ligação Proteica , Ácido Pirrolidonocarboxílico/química , Ácido Pirrolidonocarboxílico/farmacocinética , Ácido Pirrolidonocarboxílico/uso terapêutico , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Solubilidade , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 23(24): 6640-4, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24215891

RESUMO

A class of α-methyltryptamine sulfonamide glucocorticoid receptor (GR) modulators was optimized for agonist activity. The design of ligands was aided by molecular modeling, and key function-regulating pharmacophoric points were identified that are critical in achieving the desired agonist effect in cell based assays. Compound 27 was profiled in vitro and in vivo in models of inflammation. Analogs could be rapidly prepared in a parallel approach from aziridine building blocks.


Assuntos
Receptores de Glucocorticoides/agonistas , Sulfonamidas/química , Sulfonamidas/farmacologia , Triptaminas/química , Triptaminas/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Sítios de Ligação , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Triptaminas/metabolismo , Triptaminas/uso terapêutico
4.
Bioorg Med Chem Lett ; 21(22): 6842-51, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21963986

RESUMO

We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.


Assuntos
Glucocorticoides/química , Glucocorticoides/farmacologia , Indóis/química , Indóis/farmacologia , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/metabolismo , Animais , Células HeLa , Humanos , Camundongos , Modelos Moleculares , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 19(9): 2386-91, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19356929

RESUMO

An effort aimed at exploring structural diversity in the N-pyrazole-N'-naphthylurea class of p38 kinase inhibitors led to the synthesis and characterization of N-phenyl-N'-naphthylureas. Examples of these compounds displayed excellent inhibition of TNF-alpha production in vitro, as well as efficacy in a mouse model of lipopolysaccharide induced endotoxemia. In addition, perspective is provided on the role of a sulfonamide functionality in defining inhibitor potency.


Assuntos
2-Naftilamina/análogos & derivados , Inibidores de Proteínas Quinases/farmacologia , Ureia/análogos & derivados , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , 2-Naftilamina/química , Animais , Química Orgânica/métodos , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Desenho de Fármacos , Concentração Inibidora 50 , Lipopolissacarídeos/metabolismo , Camundongos , Modelos Químicos , Estrutura Molecular , Fator de Necrose Tumoral alfa/metabolismo , Ureia/química
7.
J Med Chem ; 57(4): 1583-98, 2014 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-24506830

RESUMO

Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21. These compounds maintained anti-inflammatory activity in vivo in collagen induced arthritis studies in mouse but had reduced effects on bone relevant parameters compared to the widely used synthetic glucocorticoid prednisolone 2 in vivo. To our knowledge, we are the first to report on selective glucocorticoid ligands with reduced bone loss in a preclinical in vivo model.


Assuntos
Osso e Ossos/efeitos dos fármacos , Receptores de Glucocorticoides/agonistas , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 17(15): 4242-7, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17560108

RESUMO

Discovery of the pyrazole-naphthyl urea class of p38 MAP kinase inhibitors typified by the clinical candidate BIRB 796 has encouraged further exploration of this particular scaffold. Modification to the part of the inhibitor that occupies the adenine/ATP binding site has resulted in a new way to obtain potent inhibitors that possess favorable in vitro and in vivo properties.


Assuntos
Adenina/metabolismo , Inibidores de Proteínas Quinases/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Sítios de Ligação , Humanos , Modelos Moleculares , Inibidores de Proteínas Quinases/metabolismo , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Bioorg Med Chem Lett ; 17(9): 2465-9, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17379516

RESUMO

The synthesis and in vitro activities of a series of succinyl-nitrile-based inhibitors of Cathepsin S are described. Several members of this class show nanomolar inhibition of the target enzyme as well as cellular potency. The inhibitors displaying the greatest potency contain N-alkyl substituted piperidine and pyrrolidine rings spiro-fused to the alpha-carbon of the P1 residue.


Assuntos
Catepsinas/antagonistas & inibidores , Química Farmacêutica/métodos , Nitrilas/química , Domínio Catalítico , Dipeptídeos/química , Desenho de Fármacos , Humanos , Modelos Químicos , Conformação Molecular , Nitrilas/classificação , Peptídeos/química , Piperidinas/química , Pirrolidinas/química , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 15(21): 4761-9, 2005 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-16112571

RESUMO

Compound 1, a potent glucocorticoid receptor ligand, contains a quaternary carbon bearing trifluoromethyl and hydroxyl groups. This paper describes the effect of replacing the trifluoromethyl group on binding and agonist activity of the GR ligand 1. The results illustrate that replacing the CF3 group with a cyclohexylmethyl or benzyl group maintains the GR binding potency. These substitutions alter the functional behavior of the GR ligands from agonists to antagonists. Docking studies suggest that the benzyl analog 19 binds in a similar fashion as the GR antagonist, RU486. The central benzyl group of 19 and the C-11 dimethylaniline moiety of RU486 overlay. Binding of compound 19 is believed to force helix 12 to adopt an open conformation and this leads to the antagonist properties of the non-CF3 ligands carrying a large group at the center of the molecule.


Assuntos
Clorofluorcarbonetos de Metano/química , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/antagonistas & inibidores , Células Cultivadas , Clorofluorcarbonetos de Metano/farmacologia , Fibroblastos , Células HeLa , Humanos , Interleucina-6/biossíntese , Interleucina-6/genética , Ligantes , Modelos Moleculares , Ligação Proteica , Conformação Proteica/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacos
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