RESUMO
OBJECTIVE: Irisin is known to be an important metabolic regulator of glucose and lipid metabolism. The aims of the present study are to assess the role of mouse Irisin in obesity and energy metabolism and its glucose and lipid-lowering effects in a high-fat diet-induced obesity (DIO) mice model. METHODS: DIO mice were treated with recombinant murine Irisin or vehicle, and parameters such as body weight, feed intake, glucose, and lipid levels, obesity, energy consumption, and insulin sensitivity were assessed. mRNA and protein levels of UCP1 and different thermogenesis biomarker were evaluated by quantitative real-time PCR and Western blot, respectively, in tissues and major metabolic organs. RESULTS: Irisin decreased body weight and whole-body fat mass in DIO mice in a dose dependent manner due to marked increases in total energy expenditure. It also lowered blood glucose, insulin, and lipid levels and possibly reversed hepatic steatosis. Irisin improved hepatic and peripheral insulin sensitivity in DIO mice along with body weight reduction and adiposity. Gene expression of UCP1 in different organs (adipose tissue and major organs, i.e., liver, kidney, heart, brain, and spleen) have suggested the role of irisin is global. Gene expression profile of different biomarkers in spleen suggest a profound role of Irisin in inflammation. Liver tissue have also shown significant increase of UCP1 expression in dose dependent manner which suggest a role of irisin in liver.
Assuntos
Dieta Hiperlipídica , Metabolismo Energético , Fibronectinas/metabolismo , Termogênese , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Proteínas Recombinantes/metabolismo , Redução de PesoRESUMO
Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (-)-12a, (-)-12i, (-)-12l-m. The required (-)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15. Based on comparative profile of FAAH potency, metabolic stability in liver microsome, liability of inhibiting major hCYP450 isoforms, rat PK, and brain penetration ability, two SAR optimized compounds, (-)-12l and (-)-12m, were selected for efficacy study in rat model of chemotherapy-induced peripheral neuropathy (CIPN). Both the compounds exhibited dose related antihyperalgesic effects, when treated with 3-30â¯mg/kg po for 7â¯days. The effects at 30â¯mg/kg are comparable to that of PF-04457845 (10â¯mg/kg) and Tramadol (40â¯mg/kg).
Assuntos
Amidoidrolases/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Neuralgia/tratamento farmacológico , Amidoidrolases/metabolismo , Animais , Antineoplásicos/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Estrutura Molecular , Neuralgia/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Targeting nuclear receptor RORγ is recognized to be beneficial in multiple autoimmune disorders. We disclosed new indole analogues as potent RORγ inverse agonists. RO-2 as one of the potent and orally bioavailable compounds was evaluated in various models of autoimmune disorder. It showed potent suppression of downstream markers of RORγt activity in murine and human primary cells, ex vivo PD assay and in multiple animal models of autoimmune diseases. The results indicate the potential of these indole analogues as orally bioavailable small molecule inverse agonists of RORγt, efficacious in various Th17 driven models of autoimmune disorders.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Indóis/química , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Animais , Humanos , Camundongos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
1. Budesonide, a potent topical corticosteroid, reported to have low oral bioavailability in mice, rat, dog and human due to rapid first pass metabolism. However, there is insufficient information available in literature regarding the role of intestine and or liver responsible for the first pass metabolism of budesonide. 2. Current study in rats investigates the role of intestine and liver in first pass metabolism of budesonide using two in vivo models. Additionally, budesonide was also evaluated in in vitro assays such as thermodynamic solubility, permeability in Caco-2 cells and stability in simulated gastric (SGF), intestinal fluids (SIF) to understand the underlaying cause for low oral bioavailability. 3. Budesonide showed low oral, intra-duodenal and high intra-portal bioavailability in rat. In a dual vein cannulated rat model, intestinal and hepatic extraction ratios calculated based upon intestinal availability (Fa·Fg) and hepatic availability (Fh), suggests hepatic extraction of budesonide is minimal compared to intestinal. 4. In vitro results suggest, solubility and permeability may not be a barrier for the observed low oral bioavailability in rats. 5. Correlating the in vitro and in vivo data together, it can be concluded that, intestine might be playing major role in first pass metabolism of budesonide.
Assuntos
Budesonida/farmacologia , Budesonida/farmacocinética , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Animais , Células CACO-2 , Humanos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
In a pursuit to identify reversible and selective BTK inhibitors, two series based on 7H-pyrrolo[2,3-d]pyrimidine and 1H-pyrrolo[2,3-b]pyridine as the hinge binding core, have been identified. Structure activity relationship (SAR) exploration led to identification of two advanced lead molecules, 11 and 13, which demonstrated desired BTK inhibitory potency in different cellular assays, excellent selectivity in a panel of 50 diverse kinases, favorable in vivo PK properties in mice and anti-arthritic effect in a mouse model of CIA.
Assuntos
Antirreumáticos/química , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridinas/química , Piridinas/uso terapêutico , Pirróis/química , Pirróis/uso terapêutico , Tirosina Quinase da Agamaglobulinemia , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Reumatoide/enzimologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismo , Piridinas/farmacocinética , Piridinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of terminal nonyl chain and nucleobase modified analogues of (+)-EHNA (III) were synthesized and evaluated for their ability to inhibit adenosine deaminase (ADA). The constrained carbon analogues of (+)-EHNA, 7a-7h, 10a-c, 12, 13, 14 and 17a-c appeared very potent with Ki values in the low nanomolar range. Thio-analogues of (+)-EHNA 24a-e wherein 5'C of nonyl chain replaced by sulfur atom found to be less potent compared to (+)-EHNA. Docking of the representative compounds into the active site of ADA was performed to understand structure-activity relationships. Compounds 7a (Ki: 1.1nM) 7b (Ki: 5.2nM) and 26a (Ki: 5.9nM) showed suitable balance of potency, microsomal stability and demonstrated better pharmacokinetic properties as compared to (+)-EHNA and therefore may have therapeutic potential for various inflammatory diseases, hypertension and cancer.
Assuntos
Adenina/análogos & derivados , Inibidores de Adenosina Desaminase/química , Adenina/síntese química , Adenina/química , Adenina/farmacocinética , Adenina/farmacologia , Inibidores de Adenosina Desaminase/síntese química , Inibidores de Adenosina Desaminase/farmacocinética , Inibidores de Adenosina Desaminase/farmacologia , Domínio Catalítico , Ativação Enzimática/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Multipronged approach was used to synthesize a library of diverse C-8 cyclopentyl hypoxanthine analogs from a common intermediate III. Several potent and selective compounds were identified and evaluated for pharmacokinetic (PK) properties in Wistar rats. One of the compounds 14 with acceptable PK parameters was selected for testing in in vivo primary acute diuresis model. The compound demonstrated significant diuretic activity in this model.
Assuntos
Antagonistas do Receptor A1 de Adenosina/química , Antagonistas do Receptor A1 de Adenosina/farmacologia , Hipoxantinas/química , Hipoxantinas/farmacologia , Antagonistas do Receptor A1 de Adenosina/síntese química , Antagonistas do Receptor A1 de Adenosina/farmacocinética , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cromatografia Líquida , Desenho de Fármacos , Células HEK293 , Humanos , Hipoxantinas/síntese química , Hipoxantinas/farmacocinética , Masculino , Espectrometria de Massas , Espectroscopia de Prótons por Ressonância Magnética , Ensaio Radioligante , Ratos , Ratos WistarRESUMO
Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.
Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Ácidos Carboxílicos/química , Inibidores Enzimáticos/química , Pirazóis/química , Tiofenos/química , Oxirredutases do Álcool/metabolismo , Animais , Sítios de Ligação , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacocinética , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Rim/enzimologia , Rim/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Estrutura Terciária de Proteína , Pirazóis/síntese química , Pirazóis/uso terapêutico , Ratos , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/uso terapêuticoRESUMO
GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 µM)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5 g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; >100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; >100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay.
Assuntos
Descoberta de Drogas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/síntese química , Administração Oral , Animais , Concentração Inibidora 50 , Masculino , Estrutura Molecular , Ratos , Ratos Wistar , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
A novel, highly potent, orally active, nonsteroidal tissue selective androgen receptor (AR) modulator (BMS-564929) has been identified, and this compound has been advanced to clinical trials for the treatment of age-related functional decline. BMS-564929 is a subnanomolar AR agonist in vitro, is highly selective for the AR vs. other steroid hormone receptors, and exhibits no significant interactions with SHBG or aromatase. Dose response studies in castrated male rats show that BMS-564929 is substantially more potent than testosterone (T) in stimulating the growth of the levator ani muscle, and unlike T, highly selective for muscle vs. prostate. Key differences in the binding interactions of BMS-564929 with the AR relative to the native hormones were revealed through x-ray crystallography, including several unique contacts located in specific helices of the ligand binding domain important for coregulatory protein recruitment. Results from additional pharmacological studies effectively exclude alternative mechanistic contributions to the observed tissue selectivity of this unique, orally active androgen. Because concerns regarding the potential hyperstimulatory effects on prostate and an inconvenient route of administration are major drawbacks that limit the clinical use of T, the potent oral activity and tissue selectivity exhibited by BMS-564929 are expected to yield a clinical profile that provides the demonstrated beneficial effects of T in muscle and other tissues with a more favorable safety window.
Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Músculo Esquelético/efeitos dos fármacos , Próstata/efeitos dos fármacos , Pirróis/síntese química , Pirróis/farmacologia , Receptores Androgênicos/metabolismo , Testosterona/análogos & derivados , Envelhecimento/metabolismo , Animais , Aromatase/metabolismo , Ligação Competitiva , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , Di-Hidrotestosterona/química , Di-Hidrotestosterona/metabolismo , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Humanos , Imidazóis/metabolismo , Ligantes , Hormônio Luteinizante/sangue , Masculino , Músculo Esquelético/fisiologia , Orquiectomia , Próstata/fisiologia , Estrutura Terciária de Proteína , Pirróis/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/química , Receptores Androgênicos/genética , Testosterona/química , Testosterona/metabolismo , Transcrição Gênica/fisiologiaRESUMO
Muraglitazar, a novel dual (alpha/gamma) peroxisome proliferator-activated receptor (PPAR) activator, was investigated for its antidiabetic properties and its effects on metabolic abnormalities in genetically obese diabetic db/db mice. In db/db mice and normal mice, muraglitazar treatment modulates the expression of PPAR target genes in white adipose tissue and liver. In young hyperglycemic db/db mice, muraglitazar treatment (0.03-50 mg . kg(-1) . day(-1) for 2 weeks) results in dose-dependent reductions of glucose, insulin, triglycerides, free fatty acids, and cholesterol. In older hyperglycemic db/db mice, longer-term muraglitazar treatment (30 mg . kg(-1) . day(-1) for 4 weeks) prevents time-dependent deterioration of glycemic control and development of insulin deficiency. In severely hyperglycemic db/db mice, muraglitazar treatment (10 mg . kg(-1) . day(-1) for 2 weeks) improves oral glucose tolerance and reduces plasma glucose and insulin levels. In addition, treatment increases insulin content in the pancreas. Finally, muraglitazar treatment increases abnormally low plasma adiponectin levels, increases high-molecular weight adiponectin complex levels, reduces elevated plasma corticosterone levels, and lowers elevated liver lipid content in db/db mice. The overall conclusions are that in db/db mice, the novel dual (alpha/gamma) PPAR activator muraglitazar 1) exerts potent and efficacious antidiabetic effects, 2) preserves pancreatic insulin content, and 3) improves metabolic abnormalities such as hyperlipidemia, fatty liver, low adiponectin levels, and elevated corticosterone levels.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicina/análogos & derivados , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Oxazóis/uso terapêutico , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Adiponectina/sangue , Animais , Glicemia/efeitos dos fármacos , Corticosterona/sangue , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Dieta , Feminino , Glicina/farmacologia , Glicina/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/farmacologia , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Fígado , Camundongos , Obesidade , Oxazóis/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Rosiglitazona , Tiazolidinedionas/uso terapêuticoRESUMO
A2BAdoR is a low affinity adenosine receptor that functions by Gs mediated elevation of cAMP and subsequent downstream signaling. The receptor has been implicated in lung inflammatory disorders like COPD and asthma. Several potent and selective A2BAdoR antagonists have been reported in literature, however most of the compounds suffer from poor pharmacokinetic profile. Therefore, with the aim to identify novel, potent and selective A2BAdoR antagonists with improved pharmacokinetic properties, we first explored more constrained form of MRS-1754 (4). To improve the metabolic stability, several linker modifications were attempted as replacement of amide linker along with different phenyl or other heteroaryls between C8 position of xanthine head group and terminal phenyl ring. SAR optimization resulted in identification of two novel A2BAdoR antagonists, 8-{1-[5-Oxo-1-(4-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-xanthine (31) and 8-(1-{2-Oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-1H-pyrazol-4-yl)-1,3-dipropyl-xanthine (65), with high binding affinity (Ki = 1 and 1.5 nM, respectively) and selectivity for A2BAdoR with very good functional potency of 0.9 nM and 4 nM, respectively. Compound 31 and 65 also displayed good pharmacokinetic properties in mice with 27% and 65% oral bioavailability respectively. When evaluated in in vivo mice model of asthma, compound 65 also inhibited airway inflammation and airway reactivity in ovalbumin induced allergic asthma at 3 mpk dose.
Assuntos
Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Desenho de Fármacos , Receptor A2B de Adenosina/metabolismo , Xantina/síntese química , Xantina/farmacologia , Antagonistas do Receptor A2 de Adenosina/química , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Técnicas de Química Sintética , Masculino , Camundongos , Relação Estrutura-Atividade , Xantina/químicaRESUMO
Adenosine A2A receptor (A2AAdoR) antagonism is a nondopaminergic approach to Parkinson's disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as A2AAdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1-f]purin-2-one derivatives that displays functional antagonism of the A2A receptor with a high degree of selectivity over A1, A2B, and A3 receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound 33. Compound 33 endowed with satisfactory in vitro and in vivo pharmacokinetics properties. Compound 33 demonstrated robust oral efficacies in two commonly used models of Parkinson's disease (haloperidol-induced catalepsy and 6-OHDA lesioned rat models) and depression (TST and FST mice models).
RESUMO
Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia. An alternative approach to minimize the risk of hypoglycemia is to use liver-directed GKAs, which are reported to be advancing well in clinical development. Here, we report the discovery and structure-activity relationship (SAR) studies on a novel 2-phenoxy-acetamide series with the aim of identifying a liver-directed GKA. Incorporation of a carboxylic acid moiety as an active hepatocyte uptake recognizing element at appropriate position of 2-phenoxy-acetamide core led to the identification of 26, a potent GKA with predominant liver-directed pharmacokinetics in mice. Compound 26 on oral administration significantly reduced blood glucose levels during an oral glucose tolerance test (oGTT) performed in diet-induced obese (DIO) mice, while showing no sign of hypoglycemia in normal C57 mice over a 10-fold dose range, even when dosed at fasted condition. Together, these data demonstrate a liver-directed GKA has beneficial effect on glucose homeostasis with reduced risk of hypoglycemia.
Assuntos
Ativadores de Enzimas/química , Ativadores de Enzimas/farmacologia , Glucoquinase/metabolismo , Hiperglicemia/tratamento farmacológico , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Animais , Glicemia/metabolismo , Células Cultivadas , Ativadores de Enzimas/efeitos adversos , Ativadores de Enzimas/farmacocinética , Humanos , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Hipoglicemia/sangue , Hipoglicemia/metabolismo , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Obesos , Simulação de Acoplamento Molecular , RatosRESUMO
Adenosine induces bronchial hyperresponsiveness and inflammation in asthmatics through activation of A2B adenosine receptor (A2BAdoR). Selective antagonists have been shown to attenuate airway reactivity and improve inflammatory conditions in pre-clinical studies. Hence, the identification of novel, potent and selective A2BAdoR antagonist may be beneficial for the potential treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD). Towards this effort, we explored several prop-2-ynylated C8-aryl or heteroaryl substitutions on xanthine chemotype and found that 1-prop-2-ynyl-1H-pyrazol-4-yl moiety was better tolerated at the C8 position. Compound 59, exhibited binding affinity (Ki) of 62 nM but was non-selective for A2BAdoR over other AdoRs. Incorporation of substituted phenyl on the terminal acetylene increased the binding affinity (Ki) significantly to <10 nM. Various substitutions on terminal phenyl group and different alkyl substitutions on N-1 and N-3 were explored to improve the potency, selectivity for A2BAdoR and the solubility. In general, compounds with meta-substituted phenyl provided better selectivity for A2BAdoR compared to that of para-substituted analogs. Substitutions such as basic amines like pyrrolidine, piperidine, piperazine or cycloalkyls with polar group were tried on terminal acetylene, keeping in mind the poor solubility of xanthine analogs in general. However, these substitutions led to a decrease in affinity compared to compound 59. Subsequent SAR optimization resulted in identification of compound 46 with high human A2BAdoR affinity (Ki = 13 nM), selectivity against other AdoR subtypes and with good pharmacokinetic properties. It was found to be a potent functional A2BAdoR antagonist with a Ki of 8 nM in cAMP assay in hA2B-HEK293 cells and an IC50 of 107 nM in IL6 assay in NIH-3T3 cells. Docking study was performed to rationalize the observed affinity data. Structure-activity relationship (SAR) studies also led to identification of compound 36 as a potent A2BAdoR antagonist with Ki of 1.8 nM in cAMP assay and good aqueous solubility of 529 µM at neutral pH. Compound 46 was further tested for in vivo efficacy and found to be efficacious in ovalbumin-induced allergic asthma model in mice.
Assuntos
Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Asma/tratamento farmacológico , Receptor A2B de Adenosina/metabolismo , Xantina/química , Xantina/uso terapêutico , Antagonistas do Receptor A2 de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Animais , Asma/induzido quimicamente , Asma/metabolismo , Cães , Desenho de Fármacos , Células Hep G2 , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Ovalbumina , Ratos , Receptor A2B de Adenosina/química , Xantina/metabolismo , Xantina/farmacocinéticaRESUMO
Our initial structure-activity relationship studies on 7-methoxy-4-morpholino-benzothiazole derivatives featured by aryloxy-2-methylpropanamide moieties at the 2-position led to identification of compound 25 as a potent and selective A2A adenosine receptor (A2AAdoR) antagonist with reasonable ADME and pharmacokinetic properties. However, poor intrinsic solubility and low to moderate oral bioavailability made this series unsuitable for further development. Further optimization using structure-based drug design approach resulted in discovery of potent and selective adenosine A2A receptor antagonists bearing substituted 1-methylcyclohexyl-carboxamide groups at position 2 of the benzothiazole scaffold and endowed with better solubility and oral bioavailability. Compounds 41 and 49 demonstrated a number of positive attributes with respect to in vitro ADME properties. Both compounds displayed good pharmacokinetic properties with 63% and 61% oral bioavailability, respectively, in rat. Further, compound 49 displayed oral efficacy in 6-OHDA lesioned rat model of Parkinson diseases.
Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Benzotiazóis/farmacologia , Cicloexanóis/farmacologia , Receptor A2A de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Administração Oral , Animais , Antiparkinsonianos/síntese química , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Benzotiazóis/síntese química , Benzotiazóis/farmacocinética , Cicloexanóis/síntese química , Cicloexanóis/farmacocinética , Desenho de Fármacos , Células HEK293 , Humanos , Levodopa/farmacologia , Masculino , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
l-2-Hydroxy acid oxidase (Hao2) is a peroxisomal enzyme with predominant expression in the liver and kidney. Hao2 was recently identified as a candidate gene for blood pressure quantitative trait locus in rats. To investigate a pharmacological role of Hao2 in the management of blood pressure, selective Hao2 inhibitors were developed. Optimization of screening hits 1 and 2 led to the discovery of compounds 3 and 4 as potent and selective rat Hao2 inhibitors with pharmacokinetic properties suitable for in vivo studies in rats. Treatment with compound 3 or 4 resulted in a significant reduction or attenuation of blood pressure in an established or developing model of hypertension, deoxycorticosterone acetate-treated rats. This is the first report demonstrating a pharmacological benefit of selective Hao2 inhibitors in a relevant model of hypertension.