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1.
Proc Natl Acad Sci U S A ; 121(1): e2307086120, 2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-38147543

RESUMEN

The salt-inducible kinases (SIK) 1-3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. The lack of highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study of the optimal SIK isoform selectivity profile for suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy for developing potent SIK inhibitors that are highly selective against other kinases by engaging two differentiating features of the SIK catalytic site. This effort resulted in SIK1/2-selective probes that inhibit key intracellular proximal signaling events including reducing phosphorylation of the SIK substrate cAMP response element binding protein (CREB) regulated transcription coactivator 3 (CRTC3) as detected with an internally generated phospho-Ser329-CRTC3-specific antibody. These inhibitors also suppress production of pro-inflammatory cytokines while inducing anti-inflammatory interleukin-10 in activated human and murine myeloid cells and in mice following a lipopolysaccharide challenge. Oral dosing of these compounds ameliorates disease in a murine colitis model. These findings define an approach to generate highly selective SIK1/2 inhibitors and establish that targeting these isoforms may be a useful strategy to suppress pathological inflammation.


Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Proteínas Serina-Treonina Quinasas , Ratones , Humanos , Animales , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Citocinas , Inflamación/tratamiento farmacológico , Isoformas de Proteínas , Antiinflamatorios/farmacología , Inmunidad Innata , Factores de Transcripción
2.
J Med Chem ; 63(6): 2915-2929, 2020 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-32134643

RESUMEN

To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound 2 demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events.


Asunto(s)
Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/farmacocinética , Piridinas/farmacología , Piridinas/farmacocinética , Administración Oral , Animales , Perros , Descubrimiento de Drogas , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Inhibidores de las Cinasas Janus/administración & dosificación , Inhibidores de las Cinasas Janus/química , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Células de Riñón Canino Madin Darby , Ratones , Ratones Endogámicos C57BL , Permeabilidad , Fosforilación/efectos de los fármacos , Piridinas/administración & dosificación , Piridinas/química
3.
PLoS One ; 8(1): e53522, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23308243

RESUMEN

Genome-wide association studies (GWASs) have discovered association of several loci with Type 2 diabetes (T2D), a common complex disease characterized by impaired insulin secretion by pancreatic ß cells and insulin signaling in target tissues. However, effect of genetic risk variants on continuous glycemic measures in nondiabetic subjects mainly elucidates perturbation of insulin secretion. Also, the disease associated genes do not clearly converge on functional categories consistent with the known aspects of T2D pathophysiology. We used a systems biology approach to unravel genome to phenome correlation in T2D. We first examined enrichment of pathways in genes identified in T2D GWASs at genome-wide or lower levels of significance. Genes at lower significance threshold showed enrichment of insulin secretion related pathway. Notably, physical and genetic interaction network of these genes showed robust enrichment of insulin signaling and other T2D pathophysiology related pathways including insulin secretion. The network also overrepresented genes reported to interact with insulin secretion and insulin action targeting antidiabetic drugs. The drug interacting genes themselves showed overrepresentation of insulin signaling and other T2D relevant pathways. Next, we generated genome-wide expression profiles of multiple insulin responsive tissues from nondiabetic and diabetic patients. Remarkably, the differentially expressed genes showed significant overlap with the network genes, with the intersection showing enrichment of insulin signaling and other pathways consistent with T2D pathophysiology. Literature search led our genomic, interactomic, transcriptomic and toxicogenomic evidence to converge on TGF-beta signaling, a pathway known to play a crucial role in pancreatic islets development and function, and insulin signaling. Cumulatively, we find that GWAS genes relate directly to insulin secretion and indirectly, through collaborating with other genes, to insulin resistance. This seems to support the epidemiological evidence that environmentally triggered insulin resistance interacts with genetically programmed ß cell dysfunction to precipitate diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Estudios de Asociación Genética , Genoma Humano , Resistencia a la Insulina/genética , Células Secretoras de Insulina/metabolismo , Insulina/genética , Biología de Sistemas , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Interacción Gen-Ambiente , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/biosíntesis , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/patología , Masculino , Fenotipo , Transducción de Señal , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo
5.
Surg Infect (Larchmt) ; 9(3): 367-76, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18570578

RESUMEN

BACKGROUND: Combinations of a third-generation cephalosporin and metronidazole, with or without an aminoglycoside, often are used for the treatment of intra-abdominal infections in surgical settings. Simpler regimens that preserve an adequate spectrum of coverage, but allow easier administration and have fewer side effects, may be a more desirable option. METHODS: This randomized, open-label, active comparator study evaluated the effectiveness (non-inferiority hypothesis) of the beta-lactam/beta-lactamase inhibitor combination cefoperazone-sulbactam (2-8 g/day), compared with ceftazidime (2-6 g/day)-amikacin (15 mg/kg/day)-metronidazole (500 mg three times daily) in 154 and 152 subjects, respectively, having intra-abdominal infections. The study was conducted at 17 centers in India. RESULTS: Non-inferiority of cefoperazone-sulbactam (91.9%) compared with ceftazidime-amikacin-metronidazole (81.8%) was demonstrated for continued resolution of clinical signs and symptoms at the 30-day follow-up (primary endpoint) with a treatment difference of 10.1% (95% confidence interval 2.1%, 18.1%; pre-defined non-inferiority limit > -12.5%). Superiority of cefoperazone-sulbactam also was demonstrated for this endpoint, with significantly more subjects achieving continued resolution at the 30-day follow-up than in the comparator group (p = 0.015). On microbiologic outcomes, cefoperazone-sulbactam had higher success rates than ceftazidime-amikacin-metronidazole (92.9% vs. 80.0%). The pathogens (202 isolated) isolated most commonly were Escherichia coli (38.6%) and Klebsiella spp. (12.9%). The incidence of treatment-related adverse events was 6.5% and 16.4% in the cefoperazone-sulbactam and ceftazidime-amikacin-metronidazole groups, respectively, with more discontinuations due to treatment-related adverse events in the comparator arm (3.2% vs. 9.9%). CONCLUSION: Empirical cefoperazone-sulbactam monotherapy could be a useful adjunct to surgical intervention for intra-abdominal infections.


Asunto(s)
Absceso Abdominal/tratamiento farmacológico , Antibacterianos/uso terapéutico , Cefoperazona/uso terapéutico , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Peritonitis/tratamiento farmacológico , Sulbactam/uso terapéutico , Absceso Abdominal/microbiología , Adolescente , Adulto , Anciano , Amicacina/administración & dosificación , Amicacina/efectos adversos , Amicacina/uso terapéutico , Antibacterianos/administración & dosificación , Cefoperazona/administración & dosificación , Cefoperazona/efectos adversos , Ceftazidima/administración & dosificación , Ceftazidima/efectos adversos , Ceftazidima/uso terapéutico , Niño , Quimioterapia Combinada , Femenino , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/microbiología , Humanos , India , Masculino , Metronidazol/administración & dosificación , Metronidazol/efectos adversos , Metronidazol/uso terapéutico , Persona de Mediana Edad , Peritonitis/microbiología , Sulbactam/administración & dosificación , Sulbactam/efectos adversos , Insuficiencia del Tratamiento , Resultado del Tratamiento
6.
Diabetes ; 57(7): 1926-34, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18426860

RESUMEN

OBJECTIVE: We have developed a novel platform for display and delivery of bioactive peptides that links the biological properties of the peptide to the pharmacokinetic properties of an antibody. Peptides engineered in the MIMETIBODY platform have improved biochemical and biophysical properties that are quite distinct from those of Fc-fusion proteins. CNTO736 is a glucagon-like peptide 1 (GLP-1) receptor agonist engineered in our MIMETIBODY platform. It retains many activities of native GLP-1 yet has a significantly enhanced pharmacokinetic profile. Our goal was to develop a long-acting GLP-1 receptor agonist with sustained efficacy. RESEARCH DESIGN AND METHODS: In vitro and in vivo activity of CNTO736 was evaluated using a variety of rodent cell lines and diabetic animal models. RESULTS: Acute pharmacodynamic studies in diabetic rodents demonstrate that CNTO736 reduces fasting and postprandial glucose, decreases gastric emptying, and inhibits food intake in a GLP-1 receptor-specific manner. Reduction of food intake following CNTO736 dosing is coincident with detection of the molecule in the circumventricular organs of the brain and activation of c-fos in regions protected by the blood-brain barrier. Diabetic rodents dosed chronically with CNTO736 have lower fasting and postprandial glucose and reduced body weight. CONCLUSIONS: Taken together, our data demonstrate that CNTO736 produces a spectrum of GLP-1 receptor-dependent actions while exhibiting significantly improved pharmacokinetics relative to the native GLP-1 peptide.


Asunto(s)
Tejido Adiposo/metabolismo , Glucosa/metabolismo , Lactoferrina/farmacología , Ingeniería de Proteínas/métodos , Receptores de Glucagón/fisiología , Transferrina/farmacología , Tejido Adiposo/efectos de los fármacos , Secuencia de Aminoácidos , Alimentación Animal , Animales , Línea Celular , Receptor del Péptido 1 Similar al Glucagón , Homeostasis , Humanos , Riñón , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Obesidad/etiología , Obesidad/fisiopatología , Receptores de Glucagón/agonistas , Receptores de Glucagón/efectos de los fármacos
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