RESUMO
In a Phase 2 clinical trial, BMS-986020, a lysophosphatidic acid receptor-1 (LPA1) antagonist, produced hepatobiliary toxicity (increased ALT, AST, and ALP; cholecystitis) and increases in plasma bile acids (BA). Nonclinical investigations conducted to identify a potential mechanism(s) for this toxicity examined BMS-986020 and two LPA1 antagonists structurally distinct from BMS-986020 (BMS-986234 and BMS-986278). BMS-986020 inhibited hepatic BA efflux transporters BSEP (IC50 1.8 µM), MRP3 (IC50 22 µM), and MRP4 (IC50 6.2 µM) and inhibited BA canalicular efflux in human hepatocytes (68% at 10 µM). BMS-986020 inhibited mitochondrial function (basal and maximal respiration, ATP production, and spare capacity) in human hepatocytes and cholangiocytes at ≥10 µM and inhibited phospholipid efflux in human hepatocytes (MDR3 IC50 7.5 µM). A quantitative systems toxicology analysis (DILIsym®), considering pharmacokinetics, BA homeostasis, mitochondrial function, oxidative phosphorylation, and reactive intermediates performed for BMS-986020 recapitulated clinical findings ascribing the effects to BA transporter and mitochondrial electron transport chain inhibition. BMS-986234 and BMS-986278 minimally inhibited hepatic BA transporters (IC50 ≥20 µM) and did not inhibit MDR3 activity (IC50 >100 µM), nor did BMS-986234 inhibit BA efflux (≤50 µM) or mitochondrial function (≤30 µM) (BMS-986278 not evaluated). Multiple mechanisms may be involved in the clinical toxicity observed with BMS-986020. The data indicate that this toxicity was unrelated to LPA1 antagonism since the mechanisms that likely influenced the adverse clinical outcome of BMS-986020 were not observed with equipotent LPA1 antagonists BMS-986234 and BMS-986278. This conclusion is consistent with the lack of hepatobiliary toxicity in nonclinical and clinical safety studies with BMS-986278.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doenças do Sistema Digestório/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fígado/efeitos dos fármacos , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Ácidos e Sais Biliares/metabolismo , Transporte Biológico/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Transporte de Elétrons/fisiologia , Células HEK293 , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacosRESUMO
Lysophosphatidic acid (LPA) functions through activation of LPA receptors (LPARs). LPA-LPAR signaling has been implicated in development of fibrosis. However, the role of LPA-LPAR signaling in development of diabetic nephropathy (DN) has not been studied. We examined whether BMS002, a novel dual LPAR1 and LPAR3 antagonist, affects development of DN in endothelial nitric oxide synthase-knockout db/db mice. Treatment of these mice with BMS002 from 8 to 20 weeks of age led to a significant reduction in albuminuria, similar to that observed with renin-angiotensin system inhibition (losartan plus enalapril). LPAR inhibition also prevented the decline in GFR observed in vehicle-treated mice, such that GFR at week 20 differed significantly between vehicle and LPAR inhibitor groups (P<0.05). LPAR inhibition also reduced histologic glomerular injury; decreased the expression of profibrotic and fibrotic components, including fibronectin, α-smooth muscle actin, connective tissue growth factor, collagen I, and TGF-ß; and reduced renal macrophage infiltration and oxidative stress. Notably, LPAR inhibition slowed podocyte loss (podocytes per glomerulus ±SEM at 8 weeks: 667±40, n=4; at 20 weeks: 364±18 with vehicle, n=7, and 536±12 with LPAR inhibition, n=7; P<0.001 versus vehicle). Finally, LPAR inhibition minimized the production of 4-hydroxynonenal (4-HNE), a marker of oxidative stress, in podocytes and increased the phosphorylation of AKT2, an indicator of AKT2 activity, in kidneys. Thus, the LPAR antagonist BMS002 protects against GFR decline and attenuates development of DN through multiple mechanisms. LPAR antagonism might provide complementary beneficial effects to renin-angiotensin system inhibition to slow progression of DN.
Assuntos
Nefropatias Diabéticas/prevenção & controle , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Animais , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Modelos Animais de Doenças , Camundongos , Receptores de Ácidos Lisofosfatídicos/fisiologiaRESUMO
Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate.
Assuntos
Fármacos Antiobesidade/química , Pirazóis/química , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Meia-Vida , Humanos , Obesidade/tratamento farmacológico , Ligação Proteica , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Redução de Peso/efeitos dos fármacosRESUMO
Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 Ki=1.8 nM), demonstrated a 6.9% reduction in weight gain relative to vehicle in a rat model at 30 mg/kg after 4 days of once-daily oral treatment as a glycine prodrug. Despite a promising efficacy profile, an assessment of the biliary toxicity risk of this compound rendered this compound non-progressible.
Assuntos
Encéfalo/efeitos dos fármacos , Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Triazinas/farmacologia , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Obesidade/metabolismo , Ratos , Relação Estrutura-Atividade , Triazinas/administração & dosagem , Triazinas/químicaRESUMO
With an objective to improve the profiles of the 1st generation non-basic MCHR1 antagonists, a lean design approach of replacing the bicyclic thienopyrimidine core with a monocyclic pyrrol-2-one chemotype was examined in the context of reducing aromatic ring count, while also contemplating enhanced flexibility as a means of decreasing flat character. The new compounds exhibited potent antagonism up to the sub-nanomolar range, thereby implying that the monocyclic ring could effectively serve as an effective bioisostere of the bicyclic system. The prototype compound 2m offered benefits like improved potency, reduced half-life, and enhanced solubility, while also demonstrating >5% reduction in weight gain in rats, thereby providing proof-of-concept for this new class of compounds as anti-obesity agents.
Assuntos
Pirróis , Animais , Ratos , Relação Estrutura-Atividade , Humanos , Estrutura Molecular , Pirróis/farmacologia , Pirróis/química , Pirróis/síntese química , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Masculino , Ratos Sprague-Dawley , Receptores de SomatostatinaRESUMO
Circulating cell-free DNA from blood plasma of cancer patients can be used to non-invasively interrogate somatic tumor alterations. Here we develop MSK-ACCESS (Memorial Sloan Kettering - Analysis of Circulating cfDNA to Examine Somatic Status), an NGS assay for detection of very low frequency somatic alterations in 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance of MSK-ACCESS, we report results from 681 prospective blood samples that underwent clinical analysis to guide patient management. Somatic alterations are detected in 73% of the samples, 56% of which have clinically actionable alterations. The utilization of matched normal sequencing allows retention of somatic alterations while removing over 10,000 germline and clonal hematopoiesis variants. Our experience illustrates the importance of analyzing matched normal samples when interpreting cfDNA results and highlights the importance of cfDNA as a genomic profiling source for cancer patients.
Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Marcadores Genéticos/genética , Neoplasias/genética , Análise Mutacional de DNA/métodos , Frequência do Gene/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação/genética , Neoplasias/sangue , Neoplasias/patologiaRESUMO
The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1 Kb of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).
Assuntos
Descoberta de Drogas , Fibrose Pulmonar/tratamento farmacológico , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Estrutura Molecular , Fibrose Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Ácidos Lisofosfatídicos/metabolismo , Relação Estrutura-AtividadeRESUMO
Mammalian metallothionein (MT) genes are transcriptionally activated by the essential metal zinc as well as by environmental stresses, including toxic metal overload and redox fluctuations. In addition to playing a key role in zinc homeostasis, MT proteins can protect against metal- and oxidant-induced cellular damage, and may participate in other fundamental physiologic and pathologic processes such as cell survival, proliferation, and neoplasia. Previously, our group reported a requirement for metal-responsive transcription factor-1 (MTF-1) in hypoxia-induced transcription of mouse MT-I and human MT-IIA genes. Here, we provide evidence that the protumorigenic hypoxia-inducible transcription factor-1alpha (HIF-1alpha) is essential for induction of MT-1 by hypoxia, but not zinc. Chromatin immunoprecipitation assays revealed that MTF-1 and HIF-1alpha are both recruited to the mouse MT-I promoter in response to hypoxia, but not zinc. In the absence of HIF-1alpha, MTF-1 is recruited to the MT-I promoter but fails to activate MT-I gene expression in response to hypoxia. Thus, HIF-1alpha seems to function as a coactivator of MT-I gene transcription by interacting with MTF-1 during hypoxia. Coimmunoprecipitation studies suggest interaction between MTF-1 and HIF-1alpha, either directly or as mediated by other factors. It is proposed that association of these important transcription factors in a multiprotein complex represents a common strategy to control unique sets of hypoxia-inducible genes in both normal and diseased tissue.
Assuntos
Hipóxia Celular/fisiologia , Proteínas de Ligação a DNA/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Metalotioneína/genética , Fatores de Transcrição/fisiologia , Células 3T3 , Animais , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Transformada , Deleção de Genes , Subunidade alfa do Fator 1 Induzível por Hipóxia/deficiência , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Metalotioneína/biossíntese , Camundongos , Interferência de RNA , Zinco/farmacologia , Fator MTF-1 de TranscriçãoRESUMO
The orexigenic peptide ghrelin has been shown to have prokinetic activity in the gastrointestinal (GI) system of several species, including humans. In this series of experiments, we have evaluated the prokinetic activity of novel, small-molecule ghrelin receptor (GhrR) agonists after parenteral and peroral dosing in mice and rats. Gastric emptying, small intestinal transport, and fecal output were determined after intraperitoneal and intracerebroventricular dosing of GhrR agonists, using ghrelin as a positive control. These same parameters were evaluated after oral gavage dosing of the synthetic agonists. Regardless of dose route, GhrR agonist treatment increased gastric emptying, small intestinal transit, and fecal output. However, fecal output was only increased by GhrR agonist treatment if mice were able to feed during the stimulatory period. Thus, GhrR agonists can stimulate upper GI motility, and the orexigenic action of the compounds can indirectly contribute to prokinetic activity along the entire GI tract. The orexigenic and prokinetic effects of either ghrelin or small-molecule GhrR agonists were selective for the GhrR because they were absent when evaluated in GhrR knockout mice. We next evaluated the efficacy of the synthetic GhrR agonists dosed in a model of opiate-induced bowel dysfunction induced by a single injection of morphine. Oral dosing of a GhrR agonist normalized GI motility in opiate-induced dysmotility. These data demonstrate the potential utility of GhrR agonists for treating gastrointestinal hypomotility disorders.
Assuntos
Motilidade Gastrointestinal/efeitos dos fármacos , Grelina/administração & dosagem , Grelina/farmacologia , Hormônios Peptídicos/administração & dosagem , Hormônios Peptídicos/farmacologia , Receptores de Grelina/agonistas , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Doença de Bowen/induzido quimicamente , Doença de Bowen/tratamento farmacológico , Doença de Bowen/fisiopatologia , Sistema Nervoso Central/efeitos dos fármacos , Defecação/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Esvaziamento Gástrico/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfina/farmacologia , Hormônios Peptídicos/sangue , Ratos , Ratos Sprague-Dawley , Receptores de Grelina/genética , Receptores de Grelina/metabolismoRESUMO
The first enantioselective synthesis of (D)-2-tert-butoxycarbonylamino-5,5-difluoro-5-phenyl-pentanoic acid 3 was achieved. The incorporation of the titled compound into growth hormone secretagogue (GHS) compounds resulted in new analogs 10 and 16, both of which had significantly increased in vitro potency. The compound 10 also showed improved in vivo efficacy as well as pharmacokinetic properties in rat models.
Assuntos
Hormônio do Crescimento/metabolismo , Ácidos Pentanoicos/síntese química , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Carbamatos/farmacologia , Química Farmacêutica/métodos , Desenho de Fármacos , Indóis/farmacologia , Modelos Químicos , Ácidos Pentanoicos/química , Ácidos Pentanoicos/farmacologia , Hormônios Peptídicos/química , Ratos , Compostos de Espiro/farmacologia , Estereoisomerismo , Tetrazóis/farmacologiaRESUMO
The discovery and optimization of a novel series of prolinol-derived GHSR agonists is described. This series emerged from a 11,520-member solid-phase library targeting the GPCR protein superfamily, and the rapid optimization of low micromolar hits into single-digit nanomolar leads can be attributed to the solid-phase synthesis of matrix libraries, which revealed multiple non-additive structure-activity relationships. In addition, the separation of potent diastereomers highlighted the influence of the alpha-methyl stereochemistry of the phenoxyacetamide sidechain on GHSR activity.
Assuntos
Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores de Grelina/agonistas , Técnicas de Química Combinatória , Estrutura Molecular , Pirrolidinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of N1 substituted tetrazole amides were prepared and showed to be potent growth hormone (GH) secretagogues. Among them, hydroxyl containing analog 31 displayed excellent in vivo activity by increasing plasma GH 10-fold in an anesthetized IV rat model.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Hormônio do Crescimento/metabolismo , Tetrazóis/química , Amidas/química , Animais , Linhagem Celular , Glioma/metabolismo , Hormônio do Crescimento/sangue , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
1H-tetrazole-1-alkanenitrile SR-9g exhibits a >10-fold in vivo potency enhancement over the lead nitrile 1 and has acceptable oral bioavailability in rats and dogs. An enantiospecific synthesis of 1H-tetrazole-1-alkanenitrile nitriles 9 has been developed.
Assuntos
Hormônio do Crescimento/metabolismo , Nitrilas/farmacologia , Tetrazóis/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/farmacocinética , Hipófise , Ratos , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/farmacocinéticaRESUMO
The structure-activity relationship of the O-benzyl serine side chain was investigated based on the tetrazole-based growth hormone secretagogue BMS-317180 (2). The ortho position of the benzyl moiety was found to be favorable for introduction of substituents. A series of ortho-substituted compounds were synthesized with improved in-vitro and in-vivo activity. Among them, the biphenyl compound 2p shows twofold improvement in potency compared to its parent compound BMS-317180 (2).
Assuntos
Desenho de Fármacos , Hormônio do Crescimento/metabolismo , Serina/análogos & derivados , Tetrazóis/química , Tetrazóis/farmacologia , Animais , Carbamatos/farmacologia , Estrutura Molecular , Ratos , Serina/química , Relação Estrutura-Atividade , Tetrazóis/síntese químicaRESUMO
A tetrazole-based peptidomimetic 2 (BMS-317180) was discovered as a human growth hormone secretagogue (GHS). Compound 2 is a potent, novel, orally effective GHS that shows an excellent safety profile in preclinical studies. The compound was advanced into clinical development.
Assuntos
Carbamatos/síntese química , Hormônio do Crescimento/metabolismo , Tetrazóis/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Carbamatos/farmacocinética , Carbamatos/farmacologia , Cães , Ésteres , Hormônio do Crescimento/sangue , Hormônio do Crescimento Humano/metabolismo , Humanos , Macaca fascicularis , Ratos , Solubilidade , Relação Estrutura-Atividade , Tetrazóis/farmacocinética , Tetrazóis/farmacologia , ÁguaRESUMO
PURPOSE: The purpose of this study was to develop and validate magnetic resonance imaging (MRI) scanning of the contralateral meniscus as a more accurate method of determining the needed size of a meniscal allograft than the traditional method of inferring meniscal size from radiographic measurement of the ipsilateral tibial plateau. METHODS: Tissue bank meniscal size records from the left and right knees of 500 meniscal donors were analyzed for symmetry. The menisci of 10 cadaveric knees were then sized indirectly via the radiographic tibial plateau method and directly via MRI and actual physical measurement. The MRI and radiographic methods were then compared. Statistical analysis was carried out to determine error rates for each imaging method by comparison to the physical meniscal measurements. RESULTS: Of the 500 pairs of menisci, 97% were found to be within 3 mm of each other in both the anterior-posterior and medial-lateral dimensions. In the cadaveric study MRI measurement predicted actual meniscal size significantly better than the radiographic tibial plateau method. CONCLUSIONS: Human knee menisci are bilaterally symmetric in size. Direct MRI measurement of the contralateral intact meniscus better predicts actual meniscal size than estimation of size indirectly from measurement of the tibial plateau on which it is located. We, therefore, propose contralateral MRI meniscal measurement as a new gold standard to size menisci before transplantation. LEVEL OF EVIDENCE: Level II, diagnostic study of consecutive patients with a universally applied gold standard.
Assuntos
Imageamento por Ressonância Magnética/métodos , Meniscos Tibiais/anatomia & histologia , Meniscos Tibiais/transplante , Cadáver , Feminino , Humanos , Masculino , Meniscos Tibiais/diagnóstico por imagem , Radiografia , Tíbia/anatomia & histologia , Tíbia/diagnóstico por imagem , Tíbia/cirurgia , Transplante HomólogoRESUMO
Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.
Assuntos
Arginina/análogos & derivados , Flavonas/química , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Arginina/síntese química , Arginina/química , Arginina/farmacologia , Encéfalo/metabolismo , Células CACO-2 , Permeabilidade da Membrana Celular , Comportamento Alimentar/efeitos dos fármacos , Flavonas/síntese química , Flavonas/farmacologia , Células HEK293 , Humanos , Masculino , Membranas Artificiais , Camundongos Knockout , Microssomos Hepáticos/metabolismo , Mutação , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/genética , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding Ki and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both Gq-coupled intracellular Ca2+ flux and Gs-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.
Assuntos
Hipoglicemiantes/farmacologia , Pirrolidinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Glicemia/análise , Glicemia/metabolismo , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Ratos , Receptores Acoplados a Proteínas G/metabolismoRESUMO
The potent MCHR1 in vitro and in vivo antagonist activity of a series of cyclic tertiary alcohols derived from compound 2b is described. Subsequent pharmacokinetic and pharmacodynamic studies identified BMS-814580 (compound 10) as a highly efficacious antiobesity agent with a relatively clean in vitro and in vivo safety profile.
Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Obesidade/tratamento farmacológico , Pirimidinas/química , Pirimidinas/uso terapêutico , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Cães , Halogenação , Humanos , Macaca fascicularis , Masculino , Camundongos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Receptores de Somatostatina/metabolismo , Relação Estrutura-AtividadeRESUMO
Metal transcription factor-1 (MTF-1) is a ubiquitous transcriptional regulator and chromatin insulator with roles in cellular stress responses and embryonic development. The studies described herein establish for the first time the involvement of MTF-1 in tumor development. Genetically manipulated ras-transformed mouse embryonic fibroblasts (MEFs), wild-type (MTF-1+/+), or nullizygous for MTF-1 (MTF-1-/-) were used to develop fibrosarcoma tumors. Loss of MTF-1 resulted in delayed tumor growth associated with increased matrix collagen deposition and reductions in vasculature density. Molecular consequences of MTF-1 loss include increased expression and activation of the transforming growth factor-beta1 (TGF-beta1) and tissue transglutaminase (tTG), two proteins with documented roles in the production and stabilization of extracellular matrix (ECM). Our findings support the hypothesis that MTF-1 enhances the ability of the developing tumor mass to evade fibrosis and scarring of the tumor, a critical step in tumor cell proliferation.