RESUMO
Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the central pyridinone core led to the discovery of potent EP(3) receptor antagonists such as compound 29 which possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and DMPK properties of representative compounds are discussed.
Assuntos
Oxazóis/síntese química , Piridonas/síntese química , Receptores de Prostaglandina E Subtipo EP3/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Estrutura Molecular , Oxazóis/química , Oxazóis/farmacologia , Ligação Proteica/efeitos dos fármacos , Piridonas/química , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP3/química , Relação Estrutura-AtividadeRESUMO
A series of 3-urea-1-(phenylmethyl)-pyridones was discovered as novel EP(3) antagonists via high-throughput screening and subsequent optimization. The synthesis, structure-activity relationships, and optimization of the initial hit that resulted in potent and selective EP(3) receptor antagonists such as 11g are described.
Assuntos
Piridonas/farmacologia , Receptores de Prostaglandina E Subtipo EP3/antagonistas & inibidores , Animais , Humanos , Piridonas/química , Ratos , Relação Estrutura-AtividadeRESUMO
A series of amino acid anthranilamide derivatives identified from a high-throughput screening campaign as novel, potent, and glucose-sensitive inhibitors of human liver glycogen phosphorylase a are described. A solid-phase synthesis using Wang resin was also developed which provided efficient access to a variety of analogues, and resulted in the identification of key structure-activity relationships, and the discovery of a potent exemplar (IC(50)=80 nM). The SAR scope, synthetic strategy, and in vitro results for this series are presented herein.
Assuntos
Glicogênio Fosforilase Hepática/antagonistas & inibidores , ortoaminobenzoatos/química , Aminoácidos/química , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Glicogênio Fosforilase Hepática/química , Humanos , Concentração Inibidora 50 , Fígado/enzimologia , Microssomos Hepáticos/enzimologia , Modelos Químicos , Ratos , Relação Estrutura-Atividade , Ureia/química , ortoaminobenzoatos/farmacologiaRESUMO
A series of 3-phenyl-2-propenamides discovered from a high-throughput screening campaign as novel, potent, glucose-sensitive inhibitors of human liver glycogen phosphorylase a is described. A solid-phase synthesis on DMHB resin was also developed which provided efficient access not only to certain analogues that could not be cleanly made using more traditional means, but also to a variety of additional analogues. The SAR scope and synthetic strategy are presented herein.
Assuntos
Acrilamidas/síntese química , Acrilamidas/farmacologia , Inibidores Enzimáticos/farmacologia , Glicogênio Fosforilase/antagonistas & inibidores , Técnicas de Química Combinatória , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Humanos , Fígado/enzimologia , Resinas Sintéticas/química , Relação Estrutura-AtividadeRESUMO
Demonstration that IkappaB kinase 2 (IKK-2) plays a pivotal role in the nuclear factor-kappaB-regulated production of proinflammatory molecules by stimuli such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 suggests that inhibition of IKK-2 may be beneficial in the treatment of rheumatoid arthritis. In the present study, we demonstrate that a novel, potent (IC(50) = 17.9 nM), and selective inhibitor of human IKK-2, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), inhibits lipopolysaccharide-induced human monocyte production of TNF-alpha, IL-6, and IL-8 with an IC(50) = 170 to 320 nM. Prophylactic administration of TPCA-1 at 3, 10, or 20 mg/kg, i.p., b.i.d., resulted in a dose-dependent reduction in the severity of murine collagen-induced arthritis (CIA). The significantly reduced disease severity and delay of disease onset resulting from administration of TPCA-1 at 10 mg/kg, i.p., b.i.d. were comparable to the effects of the antirheumatic drug, etanercept, when administered prophylactically at 4 mg/kg, i.p., every other day. Nuclear localization of p65, as well as levels of IL-1beta, IL-6, TNF-alpha, and interferon-gamma, were significantly reduced in the paw tissue of TPCA-1- and etanercept-treated mice. In addition, administration of TPCA-1 in vivo resulted in significantly decreased collagen-induced T cell proliferation ex vivo. Therapeutic administration of TPCA-1 at 20 mg/kg, but not at 3 or 10 mg/kg, i.p., b.i.d., significantly reduced the severity of CIA, as did etanercept administration at 12.5 mg/kg, i.p., every other day. These results suggest that reduction of proinflammatory mediators and inhibition of antigen-induced T cell proliferation are mechanisms underlying the attenuation of CIA by the IKK-2 inhibitor, TPCA-1.
Assuntos
Amidas/uso terapêutico , Antiasmáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Citocinas/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tiofenos/uso terapêutico , Trifosfato de Adenosina/metabolismo , Amidas/farmacologia , Animais , Antiasmáticos/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/prevenção & controle , Ligação Competitiva , Proliferação de Células/efeitos dos fármacos , Quimiocinas/metabolismo , Colágeno , Citocinas/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Quinase I-kappa B , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , NF-kappa B/metabolismo , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Tiofenos/farmacologia , Fator de Transcrição RelA , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The design, synthesis, and in vitro biochemical evaluation of a class of mechanism-based inhibitors of human leukocyte elastase (HLE) that incorporate in their structure a 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold with appropriate recognition and reactivity elements appended to it is described. The synthesized compounds were found to be efficient, time-dependent inhibitors of HLE. The interaction of the inhibitors with HLE is postulated to lead to the formation of a highly reactive N-sulfonyl imine (a Michael acceptor) that arises from an enzyme-induced sulfonamide fragmentation cascade. Subsequent reaction ultimately leads to the formation of a relatively stable acyl enzyme. The results cited herein demonstrate convincingly the superiority of the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold over other scaffolds (e.g., saccharin) in the design of inhibitors of (chymo)trypsin-like serine proteases.
Assuntos
Óxidos S-Cíclicos/química , Inibidores Enzimáticos/farmacologia , Elastase de Leucócito/antagonistas & inibidores , Sulfonamidas/farmacologia , Tiazóis/química , Inibidores Enzimáticos/química , Humanos , Espectroscopia de Ressonância Magnética , Sulfonamidas/químicaRESUMO
The porphodimethene rearrangement methodology reported in this paper provides for a rational, step-by-step synthesis of chlorins from readily available pyrrole precursors. The intermediate porphodimethenes are furnished directly via the '2 + 2' MacDonald condensation, or by the less symmetry-constrained '3 + 1' condensation of a tripyrrane and bis-formyl pyrrole. The synthetic route is short and highly convergent, especially in the case of the '3 + 1' approach, and furnishes chlorins in good to moderate yields. The synthesis is highly regioselective and appears to be based on the ability of the beta-substituent to stabilize excess electron density, with an electron-neutral hydrogen or an electron-withdrawing carbonyl beta-substituent demonstrating the greatest influence on the formation of the pyrroline ring. The synthesis is highly stereoselective when epimerization of the pyrroline ring beta-carbons is possible, furnishing only the trans-reduced sterioisomer. Finally, there is substantial evidence that a fifth, axial ligand is involved in the transposition of peripheral hydrogens during the rearrangement of the pi-system from metalloporphodimethene to metallochlorin.