RESUMO
In this Letter, we report the continued optimization of the N-acyl-2-aminobenzimidazole series, focusing in particular on the N-alkyl substituent and 5-position of the benzimidazole based on the binding mode and the early SAR. These efforts led to the discovery of 16, a highly potent, selective, and orally bioavailable inhibitor of IRAK-4.
Assuntos
Descoberta de Drogas , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Benzimidazóis/química , Ativação Enzimática/efeitos dos fármacos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Ratos , Relação Estrutura-AtividadeRESUMO
While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear. Toward this end, we compared colonic CCL25 protein levels in healthy individuals to those in patients with ulcerative colitis. In addition, we determined the effect of CCR9 pharmacological inhibition in the mdr1a(-/-) mouse model of ulcerative colitis. Colon samples from patients with ulcerative colitis had significantly higher levels of CCL25 protein compared to healthy controls, a finding mirrored in the mdr1a(-/-) mice. In the mdr1a(-/-) mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon. These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation.
Assuntos
Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Receptores CCR/antagonistas & inibidores , Receptores CCR/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Colite Ulcerativa/genética , Feminino , Humanos , Técnicas In Vitro , Camundongos , Camundongos Knockout , Sulfonamidas/uso terapêuticoRESUMO
Necrotizing and crescentic GN (NCGN) with a paucity of glomerular immunoglobulin deposits is associated with ANCA. The most common ANCA target antigens are myeloperoxidase (MPO) and proteinase 3. In a manner that requires activation of the alternative complement pathway, passive transfer of antibodies to mouse MPO (anti-MPO) induces a mouse model of ANCA NCGN that closely mimics human disease. Here, we confirm the importance of C5aR/CD88 in the mediation of anti-MPO-induced NCGN and report that C6 is not required. We further demonstrate that deficiency of C5a-like receptor (C5L2) has the reverse effect of C5aR/CD88 deficiency and results in more severe disease, indicating that C5aR/CD88 engagement enhances inflammation and C5L2 engagement suppresses inflammation. Oral administration of CCX168, a small molecule antagonist of human C5aR/CD88, ameliorated anti-MPO-induced NCGN in mice expressing human C5aR/CD88. These observations suggest that blockade of C5aR/CD88 might have therapeutic benefit in patients with ANCA-associated vasculitis and GN.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/prevenção & controle , Autoantígenos/imunologia , Glomerulonefrite/prevenção & controle , Peroxidase/imunologia , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Administração Oral , Animais , Complemento C6/imunologia , Via Alternativa do Complemento , Relação Dose-Resposta a Droga , Técnicas de Introdução de Genes , Glomerulonefrite/complicações , Glomerulonefrite/imunologia , Hematúria/etiologia , Hematúria/prevenção & controle , Humanos , Imunização Passiva , Leucócitos , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/imunologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peroxidase/deficiência , Proteinúria/etiologia , Proteinúria/prevenção & controle , Receptor da Anafilatoxina C5a/deficiência , Receptor da Anafilatoxina C5a/genética , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/fisiologia , Proteínas Recombinantes de Fusão , Urina/citologiaRESUMO
The concentration of CXCL12/SDF-1 in the bloodstream is tightly regulated, given its central role in leucocyte and stem/progenitor cell egress from bone marrow and recruitment to sites of inflammation or injury. The mechanism responsible for this regulation is unknown. Here we show that both genetic deletion and pharmacological inhibition of CXCR7, a high-affinity CXCL12 receptor, caused pronounced increases in plasma CXCL12 levels. The rise in plasma CXCL12 levels was associated with an impairment in the ability of leucocytes to migrate to a local source of CXCL12. Using a set of complementary and highly sensitive techniques, we found that CXCR7 protein is expressed at low levels in multiple organs in both humans and mice. In humans, CXCR7 was detected primarily on venule endothelium and arteriole smooth muscle cells. CXCR7 expression on venule endothelium was also documented in immunodeficient mice and CXCR7(+/lacZ) mice. The vascular expression of CXCR7 therefore gives it immediate access to circulating CXCL12. These studies suggest that endothelial CXCR7 regulates circulating CXCL12 levels and that CXCR7 inhibitors might be used to block CXCL12-mediated cell migration for therapeutic purposes.
Assuntos
Quimiocina CXCL12/imunologia , Endotélio Vascular/imunologia , Regulação da Expressão Gênica/imunologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Receptores CXCR/imunologia , Animais , Movimento Celular/imunologia , Quimiocina CXCL12/sangue , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Leucócitos/citologia , Leucócitos/imunologia , Leucócitos/metabolismo , Camundongos , Especificidade de Órgãos/imunologia , Receptores CXCR/biossínteseRESUMO
The chemokine CCL3/MIP-1α is a risk factor in the outcome of multiple myeloma (MM), particularly in the development of osteolytic bone disease. This chemokine, highly overexpressed by MM cells, can signal mainly through 2 receptors, CCR1 and CCR5, only 1 of which (CCR1) is responsive to CCL3 in human and mouse osteoclast precursors. CCR1 activation leads to the formation of osteolytic lesions and facilitates tumor growth. Here we show that formation of mature osteoclasts is blocked by the highly potent and selective CCR1 antagonist CCX721, an analog of the clinical compound CCX354. We also show that doses of CCX721 selected to completely inhibit CCR1 produce a profound decrease in tumor burden and osteolytic damage in the murine 5TGM1 model of MM bone disease. Similar effects were observed when the antagonist was used prophylactically or therapeutically, with comparable efficacy to that of zoledronic acid. 5TGM1 cells were shown to express minimal levels of CCR1 while secreting high levels of CCL3, suggesting that the therapeutic effects of CCX721 result from CCR1 inhibition on non-MM cells, most likely osteoclasts and osteoclast precursors. These results provide a strong rationale for further development of CCR1 antagonists for the treatment of MM and associated osteolytic bone disease.
Assuntos
Quimiocinas/farmacologia , Quimiocinas/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Osteólise/tratamento farmacológico , Receptores CCR1/antagonistas & inibidores , Carga Tumoral/efeitos dos fármacos , Administração Oral , Animais , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Quimiocinas/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Imunocompetência/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Mieloma Múltiplo/complicações , Mieloma Múltiplo/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteólise/complicações , Osteólise/patologia , Ratos , Receptores CCR1/metabolismoRESUMO
Chemokine (C-C motif) receptor 2 (CCR2) is central for the migration of monocytes into inflamed tissues. The novel CCR2 antagonist CCX140-B, which is currently in two separate phase 2 clinical trials in diabetic nephropathy, has recently been shown to reduce hemoglobin A1c and fasting blood glucose levels in type 2 diabetics. In this report, we describe the effects of this compound on glycemic and renal function parameters in diabetic mice. Since CCX140-B has a low affinity for mouse CCR2, transgenic human CCR2 knockin mice were generated and rendered diabetic with either a high-fat diet (diet-induced obesity) or by deletion of the leptin receptor gene (db/db). CCX140-B treatment in both models resulted in decreased albuminuria, which was associated with decreased glomerular hypertrophy and increased podocyte density. Moreover, treatment of diet-induced obese mice with CCX140-B resulted in decreased levels of fasting blood glucose and insulin, normalization of homeostatic model assessment of insulin resistance values, and decreased numbers of adipose tissue inflammatory macrophages. Unlike other CCR2 antagonists, CCX140-B had no effect on plasma levels of the CCR2 ligand CCL2 or on the numbers of blood monocytes. These results support the ongoing evaluation of this molecule in diabetic subjects with impaired renal function.
Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Rim/efeitos dos fármacos , Receptores CCR2/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Nefropatias Diabéticas/genética , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Resistência à Insulina , Testes de Função Renal , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores CCR2/genéticaRESUMO
The following manuscript was published as a Fast Forward article on February 29, 2012: Sullivan TJ, Dairaghi DJ, Krasinski A, Miao Z, Wang Y, Zhao BN, Baumgart T, Berahovich R, Ertl LS, Pennell A, Seitz L, Miao S, Ungashe S, Wei Z, Johnson D, Boring L, Tsou C-L, Charo IF, Bekker P, Schall TJ, and Jaen JC, Characterization of CCX140-B, an orally bioavailable antagonist of the CCR2 chemokine receptor, for the treatment of type 2 diabetes and associated complications. J Pharmacol Exp Ther jpet.111.190918; doi:10.1124/jpet.111.190918 It was later found that the chemical identity of a compound cited in the article, CCX140-B, was not sufficiently disclosed. The authors are unable, at this time, to provide the chemical identity of CCX140-B in accordance with the editorial policies of The Journal of Pharmacology and Experimental Therapeutics. As a result, the authors have voluntarily withdrawn this manuscript from publication. We apologize for any inconvenience this may cause JPET's readers.
RESUMO
A novel series of benzenesulfonanilide derivatives of 11ß-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11ß-HSD1 SPA IC(50)=1.8 and 1.4 nM, respectively).
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Anilidas/química , Compostos de Anilina/química , Inibidores Enzimáticos/química , Piperazinas/química , Sulfonamidas/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/farmacologia , Anilidas/síntese química , Compostos de Anilina/síntese química , Compostos de Anilina/farmacologia , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Células HEK293 , Humanos , Conformação Molecular , Piperazina , Piperazinas/síntese química , Piperazinas/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , TransfecçãoRESUMO
Two classes of ACK1 inhibitors, 4,5,6-trisubstituted furo[2,3-d]pyrimidin4-amines and 4,5,6-trisubstituted 7H-pyrrolo[2,3-d]pyrimidin-4-amines, were discovered and evaluated as ACK1 inhibitors. Further structural refinement led to the identification of potent and selective dithiolane inhibitor 37.
Assuntos
Furanos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Since the discovery that CXCR7 binds to CXCL12/SDF-1α, the role of CXCR7 in CXCL12-mediated biological processes has been under intensive scrutiny. However, there is no consensus in the literature on the expression of CXCR7 protein by peripheral blood cells. In this study we analyzed human and mouse leukocytes and erythrocytes for CXCR7 protein expression, using a competitive CXCL12 binding assay as well as by flow cytometry and immunohistochemistry using multiple CXCR7 Abs. CXCR7(-/-) mice were used as negative controls. Together, these methods indicate that CXCR7 protein is not expressed by human peripheral blood T cells, B cells, NK cells, or monocytes, or by mouse peripheral blood leukocytes. CXCR7 protein is, however, expressed on mouse primitive erythroid cells, which supply oxygen to the embryo during early stages of development. These studies therefore suggest that, whereas CXCR7 protein is expressed by primitive RBCs during murine embryonic development, in adult mammals CXCR7 protein is not expressed by normal peripheral blood cells.
Assuntos
Eritrócitos/metabolismo , Leucócitos/metabolismo , Receptores CXCR/biossíntese , Adulto , Animais , Separação Celular , Embrião de Mamíferos , Citometria de Fluxo , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase ReversaAssuntos
Quimiocinas CC/metabolismo , Monócitos/metabolismo , Pólipos Nasais/imunologia , Peptídeo Hidrolases/metabolismo , Processamento de Proteína Pós-Traducional , Rinite/imunologia , Sinusite/imunologia , Biomarcadores/metabolismo , Western Blotting , Quimiocinas CC/imunologia , Doença Crônica , Humanos , Monócitos/imunologia , Pólipos Nasais/etiologia , Peptídeo Hidrolases/imunologia , Rinite/complicações , Sinusite/complicaçõesRESUMO
BACKGROUND: Migration of metastatic tumor cells from the bloodstream into lymph nodes is thought to be facilitated by expression of the chemokine receptors CCR7, CXCR4 and, for B cell-derived tumors, CXCR5. Expression of their respective chemokine ligands (CCL19, CCL21, CXCL12 and CXCL13) by endothelial cells inside the lymph nodes facilitates the trans-endothelial migration (TEM) of these cells through high endothelial venules into the lymph node parenchyma. It is known that CXCR7, a second CXCL12 receptor, regulates TEM of CXCR4+CXCR7+ tumor cells towards a CXCL12 source. In this study, we set out to assess the potential stimulation by CXCL12 of tumor cell TEM towards other chemokines and whether CXCR7 might be able to regulate such effects. METHODS: The human Burkitt's lymphoma cell line NC-37, which expresses CXCR4, CXCR5, CXCR7 and CCR7, was selected as a model system. TEM of these cells through a human HUVEC endothelial cell monolayer was used as the main model system for these studies. Regulation of their TEM behavior by various concentrations of the various cognate chemokines for the above-mentioned receptors, placed in either the source or target wells of modified Boyden chamber migration plates, was assessed by quantifying the number of cells migrated under each experimental condition. RESULTS: Exposure of CXCR4âºCXCR7⺠cancer cells to CXCL12 greatly potentiated their TEM towards the chemokines CCL19 and CXCL13. This CXCL12-potentiated TEM was inhibited by the second CXCR7 chemokine ligand, CXCL11, as well as CXCR7-specific small molecule antagonists and antibodies. In contrast, the CXCR4 antagonist AMD3100 was less effective at inhibiting CXCL12-potentiated TEM. Thus, CXCR7 antagonists may be effective therapeutic agents for blocking CXCL12-mediated migration of CXCR4âºCXCR7⺠tumor cells into lymph nodes, regardless of whether the cancer cells follow a CXCL12 gradient or whether serum CXCL12 stimulates their migration towards CCR7 and CXCR5 chemokines in the lymph nodes.
Assuntos
Neoplasias/fisiopatologia , Receptores CXCR/metabolismo , Migração Transendotelial e Transepitelial/genética , Anticorpos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Quimiocinas/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Perfilação da Expressão Gênica , Inativação Gênica , Humanos , Linfoma de Células B/fisiopatologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores CCR7/metabolismo , Receptores CXCR/antagonistas & inibidores , Receptores CXCR5/metabolismo , Migração Transendotelial e Transepitelial/efeitos dos fármacosRESUMO
The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11ß-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Benzamidas/química , Inibidores Enzimáticos/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Administração Oral , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Macaca fascicularis , Microssomos Hepáticos/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Quinolinas/química , Semicarbazidas/química , Tioureia/análogos & derivados , Animais , Cães , Feminino , Hepatócitos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Quinase I-kappa B/metabolismo , Macaca mulatta , Masculino , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Semicarbazidas/síntese química , Semicarbazidas/farmacocinética , Relação Estrutura-Atividade , Tioureia/síntese química , Tioureia/química , Tioureia/farmacocinéticaRESUMO
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Semicarbazidas/química , Animais , Cães , Feminino , Ensaios de Triagem em Larga Escala , Quinase I-kappa B/metabolismo , Masculino , Microssomos/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/química , Ratos , Semicarbazidas/síntese química , Semicarbazidas/farmacocinética , Relação Estrutura-AtividadeRESUMO
CXCR7 binds chemokines CXCL11 (I-TAC) and CXCL12 (SDF-1) but does not act as a classical chemoattractant receptor. Using CCX771, a novel small molecule with high affinity and selectivity for CXCR7, we found that, although CXCR7 is dispensable for "bare filter" in vitro chemotaxis, CXCR7 plays an essential role in the CXCL12/CXCR4-mediated transendothelial migration (TEM) of CXCR4(+)CXCR7(+) human tumor cells. Importantly, although CXCL11 is unable to stimulate directly the migration of these cells, it acts as a potent antagonist of their CXCL12-induced TEM. Furthermore, even though this TEM is driven by CXCR4, the CXCR7 ligand CCX771 is substantially more potent at inhibiting it than the CXCR4 antagonist AMD3100, which is more than 100 times weaker at inhibiting TEM when compared with its ability to block bare filter chemotaxis. Far from being a "silent" receptor, we show that CXCR7 displays early hallmark events associated with intracellular signaling. Upon cognate chemokine binding, CXCR7 associates with beta-arrestin2, an interaction that can be blocked by CXCR7-specific mAbs. Remarkably, the synthetic CXCR7 ligand CCX771 also potently stimulates beta-arrestin2 recruitment to CXCR7, with greater potency and efficacy than the endogenous chemokine ligands. These results indicate that CXCR7 can regulate CXCL12-mediated migratory cues, and thus may play a critical role in driving CXCR4(+)CXCR7(+) tumor cell metastasis and tissue invasion. CXCR7 ligands, such as the chemokine CXCL11 and the newly described synthetic molecule CCX771, may represent novel therapeutic opportunities for the control of such cells.
Assuntos
Inibição de Migração Celular/imunologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/fisiologia , Receptores CXCR/antagonistas & inibidores , Receptores CXCR/fisiologia , Transdução de Sinais/imunologia , Animais , Células CHO , Linhagem Celular , Linhagem Celular Tumoral , Quimiocina CXCL12/antagonistas & inibidores , Quimiocina CXCL12/metabolismo , Quimiotaxia de Leucócito/imunologia , Cricetinae , Cricetulus , Endotélio Vascular/metabolismo , Humanos , Ligantes , Receptores CXCR/biossíntese , Receptores CXCR/metabolismo , Receptores CXCR4/biossíntese , Células U937RESUMO
The chemokine system represents a diverse group of G protein-coupled receptors responsible for orchestrating cell recruitment under both homeostatic and inflammatory conditions. Chemokine receptor 9 (CCR9) is a chemokine receptor known to be central for migration of immune cells into the intestine. Its only ligand, CCL25, is expressed at the mucosal surface of the intestine and is known to be elevated in intestinal inflammation. To date, there are no reports of small-molecule antagonists targeting CCR9. We report, for the first time, the discovery of a small molecule, CCX282-B, which is an orally bioavailable, selective, and potent antagonist of human CCR9. CCX282-B inhibited CCR9-mediated Ca(2+) mobilization and chemotaxis on Molt-4 cells with IC(50) values of 5.4 and 3.4 nM, respectively. In the presence of 100% human serum, CCX282-B inhibited CCR9-mediated chemotaxis with an IC(50) of 33 nM, and the addition of α1-acid glycoprotein did not affect its potency. CCX282-B inhibited chemotaxis of primary CCR9-expressing cells to CCL25 with an IC(50) of 6.8 nM. CCX282-B was an equipotent inhibitor of CCL25-directed chemotaxis of both splice forms of CCR9 (CCR9A and CCR9B) with IC(50) values of 2.8 and 2.6 nM, respectively. CCX282-B also inhibited mouse and rat CCR9-mediated chemotaxis. Inhibition of CCR9 with CCX282-B results in normalization of Crohn's disease such as histopathology associated with the TNF(ΔARE) mice. Analysis of the plasma level of drug associated with this improvement provides an understanding of the pharmacokinetic/pharmacodynamic relationship for CCR9 antagonists in the treatment of intestinal inflammation.
Assuntos
Fármacos Gastrointestinais/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Receptores CCR/antagonistas & inibidores , Sulfonamidas/farmacologia , Administração Oral , Animais , Cálcio/metabolismo , Linhagem Celular , Quimiotaxia de Leucócito/efeitos dos fármacos , Doença de Crohn/tratamento farmacológico , Doença de Crohn/patologia , Fármacos Gastrointestinais/farmacocinética , Humanos , Ileíte/induzido quimicamente , Ileíte/tratamento farmacológico , Ileíte/patologia , Camundongos , Camundongos Endogâmicos C57BL , Ensaio Radioligante , Ratos , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Tretinoína/farmacologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
In this communication, human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11ß-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model.
Assuntos
Inibidores Enzimáticos/síntese química , Sulfonas/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Farmacocinética , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacocinéticaRESUMO
Discovery and optimization of a piperidyl benzamide series of 11beta-HSD1 inhibitors is described. This series was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Benzamidas/síntese química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/metabolismo , Piperidinas/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , Benzamidas/farmacologia , Cristalografia por Raios X/métodos , Desenho de Fármacos , Hepatócitos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Microssomos/metabolismo , Modelos Químicos , Estrutura Molecular , Solubilidade , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11beta-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.