RESUMO
11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) has been identified as the primary enzyme responsible for the activation of hepatic cortisone to cortisol in specific peripheral tissues, resulting in the concomitant antagonism of insulin action within these tissues. Dysregulation of 11ß-HSD1, particularly in adipose tissues, has been associated with a variety of ailments including metabolic syndrome and type 2 diabetes mellitus. Therefore, inhibition of 11ß-HSD1 with a small nonsteroidal molecule is therapeutically desirable. Implementation of a scaffold-hopping approach revealed a 3-point pharmacophore for 11ß-HSD1 that was utilized to design a 2-spiroproline derivative as a steroid mimetic scaffold. Reiterative optimization provided valuable insight into the bioactive conformation of our novel scaffold and led to the discovery of several leads, such as compounds 39 and 51. Importantly, deleterious hERG inhibition and pregnane X receptor induction were mitigated by the introduction of a 4-hydroxyl group to the proline ring system.
Assuntos
Diabetes Mellitus Tipo 2 , Síndrome Metabólica , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Hidrocortisona/metabolismoRESUMO
Inhibiting signal transduction induced by inflammatory cytokines offers a new approach for the treatment of autoimmune diseases such as rheumatoid arthritis. Kinase inhibitors have shown promising oral disease-modifying antirheumatic drug potential with efficacy similar to anti-TNF biologics. Direct and indirect inhibition of the JAKs, with small molecule inhibitors like CP-690,550 and INCB018424 or neutralizing Abs, such as the anti-IL6 receptor Ab tocilizumab, have demonstrated rapid and sustained improvement in clinical measures of disease, consistent with their respective preclinical experiments. Therefore, it is of interest to identify optimized JAK inhibitors with unique profiles to maximize therapeutic opportunities. INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM). INCB028050 inhibits intracellular signaling of multiple proinflammatory cytokines including IL-6 and IL-23 at concentrations <50 nM. Significant efficacy, as assessed by improvements in clinical, histologic and radiographic signs of disease, was achieved in the rat adjuvant arthritis model with doses of INCB028050 providing partial and/or periodic inhibition of JAK1/JAK2 and no inhibition of JAK3. Diminution of inflammatory Th1 and Th17 associated cytokine mRNA levels was observed in the draining lymph nodes of treated rats. INCB028050 was also effective in multiple murine models of arthritis, with no evidence of suppression of humoral immunity or adverse hematologic effects. These data suggest that fractional inhibition of JAK1 and JAK2 is sufficient for significant activity in autoimmune disease models. Clinical evaluation of INCB028050 in RA is ongoing.
Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/enzimologia , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Animais , Artrite Experimental/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/enzimologia , Doenças Autoimunes/imunologia , Linhagem Celular , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/fisiologia , Janus Quinase 1/fisiologia , Janus Quinase 2/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologiaRESUMO
This report describes the design and synthesis of a series of CCR2 antagonists incorporating novel non-aryl/heteroaryl RHS (right hand side) motifs. Previous SAR in the area has suggested an aryl/heteroaryl substituent as a necessary structural feature for binding to the CCR2 receptor. Herein we describe the SAR with regards to potency (binding to hCCR2), dofetilide activity and metabolic stability (in vitro HLM) for this series. The resulting outcome was the identification of compounds with excellent properties for the investigation of the role of CCR2 in disease.
Assuntos
Desenho de Fármacos , Receptores CCR2/antagonistas & inibidores , Sítios de Ligação , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
The chemokine receptor 2 (CCR2) directs migration of monocytes and has been proposed to be a drug target for chronic inflammatory diseases. INCB3344 was first published as a small molecule nanomolar inhibitor of rodent CCR2. Here, we show that INCB3344 can also bind human CCR2 (hCCR2) with high affinity, having a dissociation constant (K(d)) of approximately 5nM. The binding of the compound to the receptor is rapid and reversible. INCB3344 potently inhibits hCCR2 binding of monocyte chemoattractant protein-1 (MCP-1) and MCP-1-induced signaling and function in hCCR2-expressing cells, including ERK phosphorylation and chemotaxis, and is competitive against MCP-1 in vitro. INCB3344 also blocks MCP-1 binding to monocytes in human whole blood, with potency consistent with in vitro studies. The whole blood binding assay described here can be used for monitoring pharmacodynamic activity of CCR2 antagonists in both preclinical models and in the clinic.
Assuntos
Pirrolidinas/farmacologia , Receptores CCR2/antagonistas & inibidores , Bioensaio , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiotaxia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Citometria de Fluxo/métodos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Fosforilação , Pirrolidinas/metabolismoRESUMO
A novel series of carbamates was discovered as potent and selective HER-2 sheddase inhibitors. Significant enhancement in potency and selectivity was achieved through attenuating the P1 moiety, which was conventionally believed to be exposed to solvent.
Assuntos
Carbamatos/química , Inibidores de Proteínas Quinases/química , Receptor ErbB-2/antagonistas & inibidores , Carbamatos/síntese química , Carbamatos/farmacologia , Colagenases/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/metabolismo , Relação Estrutura-AtividadeRESUMO
A serendipitous discovery that the metalloprotease binding profile of a novel class of 2-carboxamide-3-hydroxamic acid piperidines could be significantly attenuated by the modification of the unexplored P1 substituent enabled the design and synthesis of a novel 2-carboxamide-1-hydroxamic acid cyclohexyl scaffold core that exhibited excellent HER-2 potency and unprecedented MMP-selectivity that we believe would not have been possible via conventional P1' perturbations.
Assuntos
Proteínas ADAM/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Antineoplásicos/síntese química , Ácidos Hidroxâmicos/síntese química , Proteínas de Membrana/metabolismo , Receptor ErbB-2/metabolismo , Proteína ADAM10 , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Potent and selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with several new heterocyclic P1' groups in conjunction with cyclic beta-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran beta-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC(50) value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-alpha of human whole blood. Compound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F%>90%) in rat n-in-1 PK studies.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Benzofuranos/química , Imidazóis/química , Indóis/química , Inibidores de Proteases/farmacologia , Pirazóis/química , Piridinas/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Ácidos Hidroxâmicos/química , Lipopolissacarídeos/farmacologia , Inibidores de Metaloproteinases de Matriz , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Beta-benzamido hydroxamic acids were discovered as potent TACE inhibitors. A computer model was constructed to help understanding the binding activities and guiding SAR study. SAR optimization led to the discovery of compound 30 which met all in vitro and in vivo criteria for the program and was selected for further evaluation.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas ADAM/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Administração Oral , Animais , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacologia , Sítios de Ligação , Disponibilidade Biológica , Cães , Ácidos Hidroxâmicos/farmacocinética , Modelos Moleculares , Inibidores de Proteases/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , SuínosRESUMO
Selective inhibitors of TNF-alpha Converting Enzyme (TACE) based on (1R,2S)-cyclopentyl, (3S,4S)-pyrrolidinyl, and (3R,4S)-tetrahydrofuranyl beta-benzamido hydroxamic acids have been synthesized and evaluated. This study has led to the discovery of novel inhibitors whose profiles include activity against TACE in an enzyme assay, potency in the suppression of LPS-stimulated TNF-alpha in human whole blood, selectivity against a panel of MMPs and oral bioavailability.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Proteína ADAM17 , Administração Oral , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/síntese química , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacocinética , Ratos , EstereoisomerismoRESUMO
Two novel oxaspiro[4.4]nonane beta-benzamido hydroxamic scaffolds have been synthesized in enantio- and diasteriomerically pure form. These templates proved to be exceptional platforms that have led to the discovery of potent inhibitors of TACE that are active in a cellular assay measuring suppression of LPS-induced TNF-alpha. Furthermore, these inhibitors are selective against related MMPs, demonstrate permeability in a Caco-2 assay, and display good oral bioavailability.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Alcanos/química , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Compostos de Espiro/química , Proteína ADAM17 , Administração Oral , Alcanos/síntese química , Alcanos/farmacocinética , Alcanos/farmacologia , Animais , Disponibilidade Biológica , Células CACO-2 , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacocinética , Inibidores de Metaloproteinases de Matriz , Metaloproteinases da Matriz/metabolismo , Modelos Moleculares , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Ratos Sprague-Dawley , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologiaRESUMO
Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1' substituents in conjunction with unique constrained beta-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-alpha Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-alpha in human whole blood and orally bioavailable.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Benzamidas/química , Benzamidas/farmacologia , Proteína ADAM17 , Animais , Área Sob a Curva , Benzamidas/sangue , Benzamidas/farmacocinética , Disponibilidade Biológica , Cães , Meia-Vida , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1' group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structure-activity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2' moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2' group effecting global conformational changes.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácidos Hidroxâmicos/química , Proteínas de Membrana/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Receptor ErbB-2/antagonistas & inibidores , Proteínas ADAM/metabolismo , Proteína ADAM10 , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Desenho de Fármacos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Proteínas de Membrana/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Receptor ErbB-2/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
The design, synthesis, evaluation, and identification of a novel class of (6S,7S)-N-hydroxy-6-carboxamide-5-azaspiro[2.5]octane-7-carboxamides as the first potent and selective inhibitors of human epidermal growth factor receptor-2 (HER-2) sheddase is described. Several compounds were identified that possess excellent pharmacodynamic and pharmacokinetic properties and were shown to decrease tumor size, cleaved HER-2 extracellular domain plasma levels, and potentiate the effects of the humanized anti-HER-2 monoclonal antibody (trastuzumab) in vivo in a HER-2 overexpressing cancer murine xenograft model.
Assuntos
Amidas/síntese química , Antineoplásicos/síntese química , Ácidos Hidroxâmicos/síntese química , Piperidinas/síntese química , Receptor ErbB-2/antagonistas & inibidores , Compostos de Espiro/síntese química , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Ácidos Hidroxâmicos/farmacocinética , Ácidos Hidroxâmicos/farmacologia , Camundongos , Conformação Molecular , Piperidinas/química , Piperidinas/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Transplante Heterólogo , TrastuzumabRESUMO
In this communication we describe the design, synthesis, and evaluation of novel sultam hydroxamates 4 as MMP-2, -9, and -13 inhibitors. Compound 26 was found to be an active inhibitor (MMP-2 IC(50) = 1 nM) with 1000-fold selectivity over MMP-1 and good oral bioavailability (F = 43%) in mouse. An X-ray crystal structure of 26 in MMP-13 confirms the key hydrogen bonds and prime side binding in the active site.
Assuntos
Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Sulfonamidas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Metaloproteinase 13 da Matriz , Camundongos , Modelos Moleculares , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1' site as the key area for TACE selectivity over MMPs. Rational exploration of the P1'-S1' interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1' group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.
Assuntos
Ácidos Hidroxâmicos/síntese química , Lactamas/síntese química , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/síntese química , Proteínas ADAM , Proteína ADAM17 , Administração Oral , Animais , Disponibilidade Biológica , Cães , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Lactamas/química , Lactamas/farmacologia , Metaloproteinase 3 da Matriz/química , Modelos Moleculares , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , SuínosRESUMO
Elevated levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with several inflammatory diseases, and therefore, strategies for its suppression have become important targets in drug discovery. Our efforts to suppress TNF-alpha have centered on the inhibition of TNF-alpha converting enzyme (TACE) through the use of hydroxamate inhibitors. Starting from broad-spectrum matrix metalloproteinase (MMP) inhibitors, we have designed and synthesized novel benzothiadiazepines as potent and selective TACE inhibitors. The benzothiadiazepines were synthesized with variation in P1 and P1' in order to effect potency and selectivity. The inhibitors were evaluated versus porcine TACE (pTACE), and the initial selectivity was assessed with counterscreens of MMP-1, -2, and -9. Several potent and selective inhibitors were discovered with compound 41 being the most active against pTACE (K(i) = 5 nM) while still maintaining good selectivity versus the MMP's (at least 75-fold). Most compounds were assessed in the human peripheral blood mononuclear cell assay (PBMC) and the human whole blood assay (WBA) to determine their ability to suppress TNF-alpha. Compound 32 was the most potent compound in the PBMC assay (IC(50) = 0.35 microM), while compound 62 was the most active in the WBA (IC(50) = 1.4 microM).
Assuntos
Benzodiazepinonas/síntese química , Inibidores Enzimáticos/síntese química , Ácidos Hidroxâmicos/síntese química , Metaloendopeptidases/antagonistas & inibidores , Tiazepinas/síntese química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteínas ADAM , Proteína ADAM17 , Animais , Benzodiazepinonas/química , Benzodiazepinonas/farmacologia , Proteínas Sanguíneas/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz , Modelos Moleculares , Ligação Proteica , Relação Estrutura-Atividade , Suínos , Tiazepinas/química , Tiazepinas/farmacologia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Using a pyrimidine-2,4,6-trione motif as a zinc-binding group, a series of selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) was discovered. Optimization of initial lead 1 resulted in a potent inhibitor (51), with an IC(50) of 2 nM in a porcine TACE assay. To the best of our knowledge, compound 51 and related analogues represent first examples of non-hydroxamate-based inhibitors of TACE with single digit nanomolar potency.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Barbitúricos/química , Barbitúricos/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteína ADAM17 , Barbitúricos/síntese química , Benzamidas/síntese química , Ácidos Hidroxâmicos/química , Concentração Inibidora 50 , Inibidores de Proteases/síntese químicaRESUMO
A series of novel hydantoins was designed and synthesized as structural alternatives to hydroxamate inhibitors of TACE. 5-Mono- and di-substituted hydantoins exhibited activity with IC50 values of 11-60 nM against porcine TACE in vitro and excellent selectivity against other MMPs.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Hidantoínas/síntese química , Hidantoínas/farmacologia , Proteína ADAM17 , Animais , Desenho de Fármacos , Concentração Inibidora 50 , Relação Estrutura-Atividade , Especificidade por Substrato , SuínosRESUMO
DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)) is a potent and selective inhibitor of tumor necrosis factor (TNF)-alpha-converting enzyme (TACE). It significantly inhibits lipopolysaccharide-induced soluble TNF-alpha production in blood from rodents, chimpanzee, and human, with IC(50) values ranging from 17 to 100 nM. In rodent models of endotoxemia, DPC 333 inhibited the production of TNF-alpha in a dose-dependent manner, with an oral ED(50) ranging from 1.1 to 6.1 mg/kg. Oral dosing of DPC 333 at 5.5 mg/kg daily for 2 weeks in a rat collagen antibody-induced arthritis model suppressed the maximal response by approximately 50%. DPC 333 was distributed widely to tissues including the synovium, the site of action for antiarthritic drugs. Pharmacokinetic and pharmacodynamic studies in chimpanzee revealed a systemic clearance of 0.4 l/h/kg, a V(ss) of 0.6 l/kg, an oral bioavailability of 17%, and an ex vivo IC(50) for the suppression of TNF-alpha production of 55 nM (n = 1). In a phase I clinical trial with male volunteers after single escalating doses of oral DPC 333, the terminal half-life was between 3 and 6 h and the ex vivo IC(50) for suppressing TNF-alpha production was 113 nM. Measurement of the suppression of TNF-alpha production ex vivo may serve as a good biomarker in evaluating the therapeutic efficacy of TACE inhibitors. Overall, the pharmacological profiles of DPC 333 support the notion that suppression of TNF-alpha with TACE inhibitors like DPC 333 may provide a novel approach in the treatment of various inflammatory diseases including rheumatoid arthritis, via control of excessive TNF-alpha production.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Endotoxemia/tratamento farmacológico , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Proteína ADAM17 , Adulto , Animais , Anti-Inflamatórios/sangue , Artrite Experimental/sangue , Artrite Experimental/patologia , Cães , Método Duplo-Cego , Endotoxemia/sangue , Endotoxemia/induzido quimicamente , Feminino , Humanos , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pan troglodytes , Quinolinas/sangue , Ratos , Ratos Endogâmicos , Líquido Sinovial/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangueRESUMO
A new P1' group for TACE inhibitors was identified by eliminating the oxygen atom in the linker of the original 4-(2-methylquinolin-4-ylmethoxy)phenyl P1' group. Incorporation of this 4-(2-methylquinolin-4-ylmethyl)phenyl group onto different beta-aminohydroxamic acid cores provided compound 18, which demonstrated potent porcine TACE (p-TACE) and human whole blood activity, excellent PK properties, and good selectivity against a variety of MMPs.