RESUMO
An unprecedented amount of parallel synthesis information was accumulated within Pfizer over the past 12 years. This information was captured by an informatics tool known as PGVL (Pfizer Global Virtual Library). PGVL was used for many aspects of drug discovery including automated reactant mining and reaction product formation to build a synthetically feasible virtual compound collection. In this report, PGVL is discussed in detail. The chemistry information within PGVL has been used to extract synthesis and design information using an intuitive desktop Graphic User Interface, PGVL Hub. Several real-case examples of PGVL are also presented.
Assuntos
Desenho de FármacosRESUMO
SAR studies were conducted around lead compound 1 using high-throughput parallel solution and solid phase synthesis. Our lead optimization efforts led to the identification of several CCR2b antagonists with potent activity in both binding and functional assays [Compound 71 CCR2b Binding IC(50) 3.2 nM; MCP-1-Induced Chemotaxis IC(50) 0.83 nM; Ca(2+) Flux IC(50) 7.5 nM].
Assuntos
Quimiocina CCL2/metabolismo , Quimiotaxia/efeitos dos fármacos , Pirrolidinas/farmacologia , Receptores CCR2/antagonistas & inibidores , Cálcio/metabolismo , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Fluorescência , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Rim/metabolismo , Estrutura Molecular , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Pirrolidinas/síntese química , Receptores CCR2/metabolismo , Relação Estrutura-Atividade , TransfecçãoRESUMO
N,N'-Disubstituted homopiperazine derivatives have been discovered as CC-chemokine receptor 2b (CCR2b) inhibitors with submicromolar activity in the CCR2b binding assay. A 4-substituted benzyl group on one homopiperazine nitrogen was an important moiety for binding affinity to the CCR2b receptor. The SAR for CCR2b binding affinity correlated inversely with the sigma factor of the functional group on this benzyl moiety. Introduction of hydroxy groups to appropriate positions in the 3,3-diphenylpropyl group on the other homopiperazine nitrogen increased CCR2b binding activity. The synthesis of an informer library to search for alternative substructures is also described.
Assuntos
Piperazinas/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Linhagem Celular , Quimiocina CCL2/metabolismo , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Piperazinas/química , Piperazinas/farmacologia , Ensaio Radioligante , Receptores CCR2 , Relação Estrutura-AtividadeRESUMO
Structure-activity relationships (SAR) of a weakly active class of CCR2b inhibitors were utilized to initiate a lead evolution program employing the Drug Discovery Engine. Several alternative structural series have been discovered that display nanomolar activity in the CCR2b binding and CCR2b-mediated chemotaxis assays.
Assuntos
Diaminas/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Linhagem Celular , Quimiocina CCL2/metabolismo , Quimiotaxia/efeitos dos fármacos , Técnicas de Química Combinatória , Diaminas/química , Diaminas/farmacologia , Desenho de Fármacos , Humanos , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacologia , Ensaio Radioligante , Receptores CCR2 , Relação Estrutura-AtividadeRESUMO
We describe a novel asymmetric approach using Staudinger chemistry to proline-derived spiro-beta-lactams. A chiral group at C-4 of the acid chloride of proline directs the stereoselectivity of Staudinger chemistry and later is sacrificed to obtain optically active 5.4-spiro-beta-lactams. The scope, limitations, and mechanistic rationale for the observed results of Staudinger Chemistry of the acid chloride of 4-alkyl(aryl)sulfonyloxy-l-proline with imines are also discussed.
Assuntos
Prolina/química , beta-Lactamas/síntese química , Catálise , Química Orgânica/métodos , Iminas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , EstereoisomerismoRESUMO
Chronic inflammatory diseases, such as arthritis and rheumatoid arthritis, remain major health problems worldwide. We previously demonstrated that adenosine kinase inhibitors (AKIs) exhibit antiinflammatory effects by inhibiting TNF-alpha production, neutrophil accumulation, and edema formation. Although adenosine receptor agonists produce similar effects, AKIs showed the antiinflammatory activity without the cardiovascular side effects that prevented the development of adenosine receptor specific agonists. However, previously described potent AKIs, such as 5-iodotubercidin, are nucleosides which have the potential to undergo in vivo 5'-O-phosphorylation and therefore produce cytotoxicity. In an effort to eliminate toxicities produced by phosphorylated nucleosides, l-lyxofuranosyl analogues of tubercidin were tested as potential AKIs since the opposite stereochemical orientation of the CH(2)OH was expected to eliminate intracellular phosphorylation. Described herein are the discovery of a new series of AKIs based on alpha-l-lyxofuranosyl nucleosides, their SAR, as well as the antiinflammatory activity of the lead compound GP790 (IC(50) = 0.47 nM, 47% inhibition of paw swelling at 10 mg/kg in rat carrageenan paw edema model). In addition, a study showing that in the skin lesion model the antiinflammatory activity is reversed by an A2 selective adenosine receptor antagonist 3,7-dimethyl-1-propargyl xanthine [correction of propylxanthine] (DMPX) is also described.
Assuntos
Adenosina Quinase/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/síntese química , Nucleosídeos/síntese química , Teobromina/análogos & derivados , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Contagem de Leucócitos , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Nucleosídeos/química , Nucleosídeos/farmacologia , Fosforilação , Antagonistas de Receptores Purinérgicos P1 , Ratos , Pele/efeitos dos fármacos , Pele/patologia , Relação Estrutura-Atividade , Teobromina/farmacologiaRESUMO
The arylamidrazones have been found to be potent corticotropin releasing factor (CRF) receptor antagonists structurally distinct from previously reported CRF1 antagonists. Attempts to modify the arylamidrazone core suggested an important role for the anilino NH moiety. The right-hand-side 2-nitro feature in lead 1 could be replaced with substituents methyl, chloro, cyano, or trifluoromethyl with a 4- to 10-fold reduction in receptor binding. With appropriate left-hand-side modifications, this potency loss could be recovered.