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J Med Chem ; 63(23): 15050-15071, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33261314


Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.

J Pharmacol Exp Ther ; 331(2): 349-60, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19652024


We have previously shown that inhibitors of IkappaB kinase beta (IKKbeta), including 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline (BMS-345541), are efficacious against experimental arthritis in rodents. In our efforts to identify an analog as a clinical candidate for the treatment of autoimmune and inflammatory disorders, we have discovered the potent and highly selective IKKbeta inhibitor 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066). Investigations of its pharmacology in rodent models of experimental arthritis showed that BMS-066 at doses of 5 and 10 mg/kg once daily was effective at protecting rats against adjuvant-induced arthritis, despite showing only weak inhibition at 10 mg/kg against a pharmacodymanic model of tumor necrosis factor alpha production in rats challenged with lipopolysaccharide. The duration of exposure in rats indicated that just 6 to 9 h of coverage per day of the concentration necessary to inhibit IKKbeta by 50% in vivo was necessary for protection against arthritis. Similar findings were observed in the mouse collagen-induced arthritis model, with efficacy observed at a dose providing only 6 h of coverage per day of the concentration necessary to inhibit IKKbeta by 50%. This finding probably results from the cumulative effect on multiple cellular mechanisms that contribute to autoimmunity and joint destruction, because BMS-066 was shown to inhibit a broad spectrum of activities such as T cell proliferation, B cell function, cytokine and interleukin secretion from monocytes, T(H)17 cell function and regulation, and osteoclastogenesis. Thus, only partial and transient inhibition of IKKbeta is sufficient to yield dramatic benefit in vivo, and this understanding will be important in the clinical development of IKKbeta inhibitors.

Acetamidas/farmacologia , Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Acetamidas/farmacocinética , Acetamidas/uso terapêutico , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/patologia , Autoimunidade/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Proteínas I-kappa B/metabolismo , Imunoglobulinas/biossíntese , Técnicas In Vitro , Articulações/patologia , Células Jurkat , Lipopolissacarídeos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Ligação Proteica , Ratos , Ratos Endogâmicos Lew , Fator de Necrose Tumoral alfa/biossíntese
Bioorg Med Chem Lett ; 17(5): 1233-7, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17197177


We have recently identified BMS-345541 (1) as a highly selective and potent inhibitor of IKK-2 (IC50 = 0.30 microM), which however was considerably less potent against IKK-1 (IC50 = 4.0 microM). In order to further explore the SAR around the imidazoquinoxaline tricyclic structure of 1, we prepared a series of tetracyclic analogues (7, 13, and 18). The synthesis and biological activities of these potent IKK inhibitors are described.

Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Linhagem Celular , Humanos , Concentração Inibidora 50 , Quinazolinas/síntese química , Quinazolinas/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato
J Pharmacol Exp Ther ; 315(1): 382-8, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16009742


It has previously been shown that BMS-345541 [4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline], a highly-selective inhibitor of IkappaB kinase (IKK), blocks both inflammation and joint destruction in murine collagen-induced arthritis. Although this agent has been shown to inhibit nuclear factor-kappaB-dependent cytokine expression in mice, we examined whether the inhibitor directly inhibits cytokine-driven metalloproteinase expression and cartilage degradation. In SW-1353 human chondrosarcoma cells, BMS-345541 inhibited interleukin-1 (IL-1)-dependent expression of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 in a concentration-dependent manner. IL-1 treatment failed to induce and BMS-345541 did not inhibit the expression of aggrecanases ADAMTS-4 (a disintegrin and metalloproteinase domain with thrombospondin motif) and ADAMTS-5, as well as the tissue inhibitor of metalloproteinase-3. In bovine cartilage explant cultures stimulated with IL-1 to induce aggrecan and collagen degradation over 3 weeks of culture, BMS-345541 was effective in inhibiting the degradation of both aggrecan and collagen. Secreted ADAMTS-4 was not inhibited by BMS-345541 in these explants, whereas ADAMTS-5 secretion was blocked in the same concentration range that inhibited aggrecan degradation. The ability of the IKK inhibitor to block aggrecan and collagen degradation through suppression of metalloproteinase expression, coupled with its ability to block inflammatory cytokine production, shows IKK to be a promising target for the development of novel agents to treat arthritic diseases.

Cartilagem/metabolismo , Colágeno/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Interleucina-1/farmacologia , Lectinas Tipo C/metabolismo , Metaloproteases/genética , Inibidores de Proteínas Quinases/farmacologia , Proteoglicanas/metabolismo , Proteínas ADAM/genética , Proteína ADAMTS4 , Proteína ADAMTS5 , Agrecanas , Animais , Bovinos , Condrócitos/metabolismo , Humanos , Imidazóis/farmacologia , Fosforilação , Pró-Colágeno N-Endopeptidase/genética , Quinoxalinas/farmacologia
J Biol Chem ; 278(3): 1450-6, 2003 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-12403772


The signal-inducible phosphorylation of serines 32 and 36 of I kappa B alpha is critical in regulating the subsequent ubiquitination and proteolysis of I kappa B alpha, which then releases NF-kappa B to promote gene transcription. The multisubunit I kappa B kinase responsible for this phosphorylation contains two catalytic subunits, termed I kappa B kinase (IKK)-1 and IKK-2. BMS-345541 (4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline) was identified as a selective inhibitor of the catalytic subunits of IKK (IKK-2 IC(50) = 0.3 microm, IKK-1 IC(50) = 4 microm). The compound failed to inhibit a panel of 15 other kinases and selectively inhibited the stimulated phosphorylation of I kappa B alpha in cells (IC(50) = 4 microm) while failing to affect c-Jun and STAT3 phosphorylation, as well as mitogen-activated protein kinase-activated protein kinase 2 activation in cells. Consistent with the role of IKK/NF-kappa B in the regulation of cytokine transcription, BMS-345541 inhibited lipopolysaccharide-stimulated tumor necrosis factor alpha, interleukin-1 beta, interleukin-8, and interleukin-6 in THP-1 cells with IC(50) values in the 1- to 5-microm range. Although a Dixon plot of the inhibition of IKK-2 by BMS-345541 showed a non-linear relationship indicating non-Michaelis-Menten kinetic binding, the use of multiple inhibition analyses indicated that BMS-345541 binds in a mutually exclusive manner with respect to a peptide inhibitor corresponding to amino acids 26-42 of I kappa B alpha with Ser-32 and Ser-36 changed to aspartates and in a non-mutually exclusive manner with respect to ADP. The opposite results were obtained when studying the binding to IKK-1. A binding model is proposed in which BMS-345541 binds to similar allosteric sites on IKK-1 and IKK-2, which then affects the active sites of the subunits differently. BMS-345541 was also shown to have excellent pharmacokinetics in mice, and peroral administration showed the compound to dose-dependently inhibit the production of serum tumor necrosis factor alpha following intraperitoneal challenge with lipopolysaccharide. Thus, the compound is effective against NF-kappa B activation in mice and represents an important tool for investigating the role of IKK in disease models.

Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , NF-kappa B/fisiologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Quinoxalinas/farmacologia , Transcrição Genética/efeitos dos fármacos , Sítio Alostérico , Animais , Domínio Catalítico , Inibidores Enzimáticos/metabolismo , Feminino , Quinase I-kappa B , Imidazóis/metabolismo , Cinética , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Quinoxalinas/metabolismo , Transcrição Genética/fisiologia