RESUMO
A series of N-alpha-mercaptoacetyl containing dipeptides have been prepared on solid-phase supports as putative matrix metalloprotease (MMP) inhibitors. Inhibitor design was based on a positional scanning approach of the amino acids present within a template molecule, previously shown to be an MMP inhibitor with good pharmacological characteristics. This study is the first step in a unique programme, designed to expand the repertoire of molecular templates which can be chosen as starting points for the development of more focused parallel and/or combinatorial libraries of MMP inhibitors as a means to accelerate the lead discovery process. This paper reports the success of such an approach in the development of agents with activity against a number of pathologically important MMPs. After screening of these positional scanning libraries, we have obtained important SAR information, in particular, pharmacophores with the ability to impart selectivity for particular MMP species.
Assuntos
Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/síntese química , Compostos de Sulfidrila/química , Fluorometria , Inibidores de Proteases/farmacologiaRESUMO
Hydrogen bonding interactions play a major role in many chemical and biological processes. This article describes the development of a method for the quantitative estimation of the hydrogen-bonding donor strengths of OH/NH moieties and of the hydrogen bonding acceptor strengths of O/N atoms in different chemical structures. The method is based on the correlation of experimentally observed hydrogen-bonding strengths with quantum-mechanical derived properties, calculated on the acceptor atom (for hydrogen-bond acceptors) and on the heavy atom attached to the donor hydrogen (for hydrogen-bond donors). The properties giving the best correlation with the experimental hydrogen bonding scales were electrophilic superdelocalizability and self-atom polarizability. The best equations found have been implemented in a Web-based tool for hydrogen-bond strength prediction.
Assuntos
Desenho de Fármacos , Ligação de Hidrogênio , Software , Gráficos por Computador , Simulação por Computador , Bases de Dados como Assunto , Modelos Químicos , Prótons , Teoria QuânticaRESUMO
Phosphodiesterase enzymes are responsible for the inactivation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterase 4 (PDE4) is a cAMP specific phosphodiesterase expressed in inflammatory cells such as eosinophils. Inhibition of PDE4 results in an elevation of cAMP in these cells, which in turn downregulates the inflammatory response. The anti-inflammatory effects of PDE4 inhibitors have been well documented both in vitro and in vivo in a variety of animal models. The potential use of PDE4 inhibitors as anti-inflammatory agents for the treatment of asthma and other inflammatory disorders has received considerable attention from the pharmaceutical industry, but to date, there are no selective PDE4 inhibitors on the market. Early PDE4 inhibitors, typified by rolipram, suffered from dose-limiting side effects, including nausea and emesis, which severely restricted their therapeutic utility. Second generation compounds, including CDP840 and SB207499 (Ariflo), have been identified with reduced side effect liability. Recent evidence suggests a correlation between side effects and the ability of compounds to bind at the so-called high affinity rolipram binding site (HPDE), whilst beneficial effects appear to correlate with binding at the catalytic site. A number of companies are actively pursuing compounds which exhibit improved affinity for the catalytic site and reduced affinity for the HPDE, in the expectation that this will provide compounds with an improved therapeutic index.
RESUMO
The design and synthesis of a series of analogues of sialyl Lewis(x)(1) which incorporate conformationally rigid tetralin and naphthalene ring systems(2-4) has led to novel compounds which have similar potency to 1 as inhibitors of cell adhesion.
Assuntos
Endotélio Vascular/fisiologia , Oligossacarídeos/química , Oligossacarídeos/síntese química , Configuração de Carboidratos , Sequência de Carboidratos , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Células Cultivadas , Gráficos por Computador , Desenho de Fármacos , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Fucose , Células HL-60 , Humanos , Indicadores e Reagentes , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Naftalenos , Oligossacarídeos/farmacologia , Antígeno Sialil Lewis X , Relação Estrutura-Atividade , Tetra-Hidronaftalenos , Fator de Necrose Tumoral alfa/farmacologia , Veias UmbilicaisRESUMO
The synthesis and pharmacological profile of a novel series of potent and selective phosphodiesterase type IV (PDE IV) inhibitors is described.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Antiasmáticos/síntese química , Antiasmáticos/farmacologia , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Amidas/síntese química , Amidas/farmacologia , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Eosinofilia/tratamento farmacológico , Cobaias , Quinolonas/síntese química , Quinolonas/farmacologia , Relação Estrutura-AtividadeRESUMO
Novel xanthine analogues are described which are selective PDE4 inhibitors with improved therapeutic potential over theophylline.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/síntese química , Xantinas/síntese química , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Eosinofilia/tratamento farmacológico , Furões , Cobaias , Inibidores de Fosfodiesterase/efeitos adversos , Inibidores de Fosfodiesterase/farmacologia , Dermatopatias/tratamento farmacológico , Teofilina/farmacologia , Vômito/induzido quimicamente , Xantinas/farmacologiaRESUMO
A series of novel matrix metalloproteinase inhibitors is described in which selectivity between MMP and 'sheddase' activity has been achieved and which demonstrate potent in vivo activity in models of arthritis and cancer.
Assuntos
Inibidores Enzimáticos/farmacologia , Ácidos Hidroxâmicos/farmacologia , Inibidores de Metaloproteinases de Matriz , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Modelos Animais de Doenças , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/uso terapêutico , Melanoma Experimental/tratamento farmacológico , CamundongosRESUMO
A series of novel selective phosphodiesterase 4 (PDE4) inhibitors has been developed which displays activity both in vitro and in vivo. These compounds possess good selectivity for the catalytic site of PDE4 over the high affinity Rolipram binding site. In vivo studies demonstrate a reduced propensity to display the emetic side effects which are commonly observed with PDE4 inhibitors.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Antiasmáticos/efeitos adversos , Antiasmáticos/síntese química , Antiasmáticos/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Eosinofilia/tratamento farmacológico , Cobaias , Inibidores de Fosfodiesterase/efeitos adversos , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacologia , Rolipram , Relação Estrutura-AtividadeRESUMO
Synthesis of a variety of 5,5-trans fused lactones, related to compounds found in extracts of Lantana camara, has provided a series of novel acylating inhibitors of human thrombin, trypsin, chymotrypsin and human leucocyte elastase. The most effective thrombin inhibitor is 7 with an IC50 of 130 nM and a Kobs/[1] of 4,000 M-1 s-1.
Assuntos
Lactonas/síntese química , Inibidores de Serina Proteinase/síntese química , Trombina/antagonistas & inibidores , Sítios de Ligação , Humanos , Cinética , Inibidores de Serina Proteinase/farmacologiaRESUMO
The synthesis of a novel series of guanine analogues is reported. The compounds have been assessed in vitro and some analogues have been found to be inhibitors of phosphodiesterase type 7 (PDE7).
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Guanina/síntese química , Guanina/farmacologia , Isoenzimas/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3 , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7 , Inibidores Enzimáticos/metabolismo , Guanina/análogos & derivados , Concentração Inibidora 50 , Relação Estrutura-AtividadeRESUMO
The synthesis and pharmacological profile of a novel series of 7-methoxybenzofuran-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).