Dihydropyrrolo[2,3-d]pyrimidines: Selective Toll-Like Receptor 9 Antagonists from Scaffold Morphing Efforts

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Dietary perilla oil lowers serum lipids and ovalbumin-specific IgG1, but increases total IgE levels in ovalbumin-challenged mice

Our previous studies indicated that α-linolenic acid (ALA)-rich perilla oil might alleviate bronchoalveolar inflammation. However, it failed to modulate the Th1/Th2 balance toward the Th1 pole during Th2-skewed allergic airway inflammation in mice. This study attempts to further investigate the effects of dietary perilla oil on serum lipids and immunoglobulin profiles using an ovalbumin (OVA)-challenged mouse model. The inbred female BALB/c mice were randomly divided into four groups and fed different AIN-76 feeds containing 5% corn oil (rich in linoleic acid, 18:2n-6 polyunsaturated fatty acids (PUFA), as a control diet), 5% perilla oil (rich in α-linolenic acid, 18:3n-3 PUFA) or 5% compound oil containing 50% corn oil and 50% perilla oil, respectively, for 35 consecutive days ad libitum. Experimental mice were sensitized by an intraperitoneal injection of alum-precipitated antigen containing ovalbumin on 7, 14 and 21 days after supply of the specified experimental diets. One week later, the mice were then challenged by aerosolized OVA. The results showed that dietary perilla oil administration significantly (P < 0.05) decreased the relative liver tissue weight (RTW) and serum lipid levels including triglycerides, total cholesterol, HDL- and LDL-cholesterol. However, the HDL/LDL ratio was also significantly lowered by dietary perilla oil. Dietary perilla oil markedly decreased serum OVA-specific IgG1 level and total IgA antibodies (Th2 antibodies). Unfortunately, it also increased non-specific serum IgE (Th2 antibody) levels. The results suggest that dietary perilla oil might have a moderately beneficial effect on asthmatic allergy via lowering serum lipids and OVA-specific IgG1, as well as total IgA levels. However, it failed to obviously modulate Th1/Th2 antibody levels via isotype switching of B cells from Th2 antibody to Th1 antibody.     

Discovery of Triazine Mimetics As Potent Antileishmanial Agents

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Discovery of a Positron Emission Tomography Radiotracer Selectively Targeting the BD1 Bromodomains of BET Proteins

In this paper, we report the design, synthesis, and biological evaluation of the first selective bromodomain and extra-terminal domain (BET) BD1 bromodomains of the PET radiotracer [¹⁸F]PB006. The standard compound PB006 showed high affinity and good selectivity toward BRD4 BD1 (K_d = 100 nM and 29-fold selectively for BD1 over BD2) in an in vitro binding assay. PET imaging experiments in rodents were performed to evaluate the bioactivity of [¹⁸F]PB006 in vivo. A biodistribution study of [¹⁸F]PB006 in mice revealed high radiotracer uptake in peripheral tissues, such as liver and kidney, and moderate radiotracer uptake in the brain. Further blocking studies demonstrated the significant radioactivity decreasing (20–30% reduction compared with baseline) by pretreating unlabeled PB006 and JQ1, suggesting the high binding selectivity and specificity of [¹⁸F]PB006. Our study indicated that [¹⁸F]PB006 is a potent PET probe selectively targeting BET BD1, and further structural optimization of the radiotracer is still required to improve brain uptake to support neuroepigenetic imaging.     

Radiosynthesis and evaluation of an (18)F-labeled positron emission tomography (PET) radioligand for brain histamine subtype-3 receptors based on a nonimidazole 2-aminoethylbenzofuran chemotype

A known chemotype of H(3) receptor ligand was explored for development of a radioligand for imaging brain histamine subtype 3 (H(3)) receptors in vivo with positron emission tomography (PET), namely nonimidazole 2-aminoethylbenzofurans, represented by the compound (R)-(2-(2-(2-methylpyrrolidin-1-yl)ethyl)benzofuran-5-yl)(4-fluorophenyl)methanone (9). Compound 9 was labeled with fluorine-18 (t(1/2) = 109.7 min) in high specific activity by treating the prepared nitro analogue (12) with cyclotron-produced [(18)F]fluoride ion. [(18)F]9 was studied with PET in mouse and in monkey after intravenous injection. [(18)F]9 showed favorable properties as a candidate PET radioligand, including moderately high brain uptake with a high proportion of H(3) receptor-specific signal in the absence of radiodefluorination. The nitro compound 12 was found to have even higher H(3) receptor affinity, indicating the potential of this chemotype for the development of further promising PET radioligands.     

A Novel 18F-Labeled Imidazo[2,1-b]benzothiazole (IBT) for High-Contrast PET Imaging of β-Amyloid Plaques

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苯并异硒唑酮磺酰胺类化合物的抗炎作用

目的　研究苯并异硒唑酮磺酰胺类化合物A和B抗炎作用。方法　Boyden 小室法测定中性粒细胞趋化;紫外分光光度法测定髓过氧化物酶活性;染色法测定肥大细胞脱颗粒。结果　化合物A和B均可抑制fMLPP诱导的兔外周血中性粒细胞趋化反应;外涂给药均可抑制巴豆油引起的小鼠髓过氧化物酶的升高。在10^-7～10^-5　mol.L^-1浓度下可抑制化合物48/80诱导的肥大细胞脱颗粒,并与浓度呈正相关。结论　苯并异硒唑酮磺酰胺类化合物A和B有明确的抗炎作用。     

Radiosynthesis and preliminary evaluation of an 18F-labeled tubastatin A analog for PET imaging of histone deacetylase 6

Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family because of its characteristics, namely, its cytoplasmic localization and ubiquitin binding. HDAC6 has been implicated in cancer metastasis and neurodegeneration. In the present study, we performed radiosynthesis and biological evaluation of a fluorine-18–labeled ligand [¹⁸F] 3 , which is an analog of the HDAC6-selective inhibitor tubastatin A, for positron emission tomography (PET) imaging. [¹⁸F] 3 was synthesized by a two-step reaction composed of ¹⁸F-fluorination and formation of a hydroxamic acid group. IC₅₀ values of 3 against HDAC1 and HDAC6 activities were 996 nM and 33.1 nM, respectively. A biodistribution study in mice demonstrated low brain uptake of [¹⁸F] 3 . Furthermore, bone radioactivity was stable at around 2% ID/g after injection, suggesting high tolerance to defluorination. Regarding metabolic stability, 70% of the compound was observed as the unchanged form at 30 minutes post injection in mouse plasma. A small animal PET study in mice showed that pretreatment with cyclosporine A had no effect on initial brain uptake of [¹⁸F] 3 , suggesting low brain uptake of [¹⁸F] 3 was not caused by the P-glycoprotein–mediated efflux. While PET imaging using [¹⁸F] 3 has a limitation with respect to neurodegenerative diseases, further studies evaluating its utility for certain cancers are worth evaluating.     

Lack of efficacy of curcumin on neurodegeneration in the mouse model of Niemann-Pick C1

In order to determine the efficacy of curcumin in ameliorating symptoms of neurodegeneration in the mouse model of Niemann-Pick C1, a variety of formulations and dosages of curcumin, one comparable to one previously reported as efficacious, were provided orally to Npc1^−/−mice. Plasma levels of curcumin, survival, tests of motor performance, and memory (in some cases) were performed. We found variable, but mild, increases in survival (1.5% to 18%). The greatest increased survival occurred with the highest dose (which was unformulated) while the control for the lipidated formulation (containing phosphatidylcholine and stearic acid) had an equivalent impact and other formulations, while not significantly increased, are also not statistically different in effect from the highest dose.We conclude that curcumin is not a highly efficacious treatment for neurodegeneration in Npc1^−/− mice. Phosphatidylcholine and stearic acid should be studied further.     

Discovery of novel PTP1B inhibitors with antihyperglycemic activity

Aim:

To discover and optimize a series of novel PTP1B inhibitors containing a thiazolidinone-substituted biphenyl scaffold and to further evaluate the inhibitory effects of these compounds in vitro and in vivo.

Methods:

A total of 36 thiazolidinone substituted biphenyl scaffold derivatives were prepared. An in vitro biological evaluation was done by Enzyme-based assay. The in vivo efficacy of 7Fb as an antihyperglycemic agent was evaluated in a BKS db/db diabetic mouse model with a dose of 50 mg·kg^-1·d^-1 for 4 weeks.

Results:

The in vitro biological evaluation showed that compounds 7Fb and 7Fc could increase the insulin-induced tyrosine phosphorylation of IRβ in CHO/hIR cells. In in vivo experiments, compound 7Fb significantly lowered the postprandial blood glucose, from 29.4±1.2 mmol/L with the vehicle to 24.7±0.6 mmol/L (P<0.01), and the fasting blood glucose from 27.3±1.5 mmol/L with the vehicle to 23.6±1.2 mmol/L (P<0.05).

Conclusion:

A novel series of compounds were discovered to be PTP1B inhibitors. Among them, compound 7Fb significantly lowered the postprandial and fasting glucose levels, and the blood glucose level declined more rapidly than in metformin-treated mice. Thus, 7Fb may be a potential lead compound for developing new agents for the treatment of type II diabetes.     

Coumarin and 3,4-dihydroquinolinone derivatives: Synthesis,antidepressant activity,and molecular docking studies

BackgroundCoumarin and 3,4-dihydroquinolinone nuclei are two heterocyclic rings that are important and widely exploited for the development of bioactive molecules. Here, we designed and synthesized a series of 3,4-dihydroquinolinone and coumarin derivatives (Compounds 8, 9, 11, 14, 15, 18-20, 23, 24 and 28 are new compounds) and studied their antidepressant activities.MethodsForced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant activity of the target compounds. The most active compound was used to evaluate the exploratory activity of the animals by the open-field test. 5-HT concentration was estimated to evaluate if the compound has an effect on the mouse brain, by using ELISA. A 5-HT_1A binding assay was also performed. The biological activities of the compounds were verified by molecular docking studies. The physicochemical and pharmacokinetic properties of the target compounds were predicted by Discovery Studio and ChemBioDraw Ultra.ResultsOf all the compounds tested, compound 7 showed the best antidepressant activity, which decreased the immobility time by 65.52 s in FST. However, in the open-field test, compound 7 did not affect spontaneous activity. The results of 5-HT concentration estimation in vivo showed that compound 7 may have an effect on the mouse brain. Molecular docking results indicated that compound 7 showed significant interactions with residues at the 5-HT_1A receptor using homology modeling. The results show that compound 7 exhibits good affinity for the 5-HT_1A receptor.ConclusionCoumarin and 3,4-dihydroquinolinone derivatives synthesized in this study have a significant antidepressant activity. These findings can be useful in the design and synthesis of novel antidepressants.     

The role of cyclophilin D in interspecies differences in susceptibility to hepatotoxic drug-induced mitochondrial injury

Test compound A ((5Z)-6-[(2R,3S)-3-({[(4-Chloro-2-methylphenyl)sulfonyl]amino}methyl) bicyclo[2.2.2]oct-2-yl]hex-5-enoic acid) was withdrawn from premarketing clinical trials due to severe liver injury. Intracellular accumulation of lipids (steatosis) has been observed in human-derived cells and may account for the severe hepatotoxicity. Mitochondrial β-oxidation and ketogenesis play a fundamental role in energy homeostasis. Mitochondrial dysfunction can therefore cause severe deficiency in fatty acid oxidation and apoptosis which finally triggers the hepatocellular injury. Some of hepatotoxic drugs (e.g., salicylic acid, diclofenac and troglitazone) are known to induce mitochondrial dysfunction. This study therefore examined the effect of compound A on the mitochondrial permeability transition (MPT) and membrane potential in mitochondria isolated from mouse, rat and monkey livers. The incubation of rat and monkey mitochondria energized by succinate in the presence of Ca²⁺ (20 μM) and compound A (2.5–10 μM) resulted in cyclosporin A (CsA)-sensitive MPT pore opening and a decline in mitochondrial membrane potential in a concentration-dependent manner. However, mouse mitochondria showed low susceptibility to compound A-induced dysfunction. Rat mitochondrial expression of cyclophilin D (CyPD) was about twice that of mouse mitochondria, but the expression levels of other MPT pore proteins (adenine nucleotide translocator and voltage-dependent anion channel) were comparable in both species. An assessment of the effect of compound A on CyPD knockdown cells demonstrated that mitochondrial susceptibility to compound A was attenuated in CyPD knockdown cells. These results suggest that an interspecies difference in the susceptibility to mitochondrial dysfunction induced by compound A exists as a result of species-specific discrepancies in CyPD expression.     

Synthesis,in vitro and in vivo giardicidal activity,and pharmacokinetic profile of a new nitazoxanide analog

4-Nitro-N-(5-nitro-1,3-thiazol-2-yl)benzamide (1), a new nitazoxanide analog, was synthesized; its chemical structure was confirmed by ¹H, ¹³C NMR, and HRMS. In this study, we evaluated the in vitro activity of compound 1 against Giardia lamblia trophozoites, as well as its in vivo giardicidal activity in a CD-1 mouse model. A pharmacokinetic study in Wistar rats evaluated compound 1 disposition after intravenous (IV) and oral administration of 3.3 and 150 mg/kg, respectively. Compound 1 inhibited G. lamblia growth in vitro with a median inhibitory concentration (IC₅₀) of 0.78 ± 0.01 μM, and thus was more effective than metronidazole (IC₅₀ = 5.36 ± 0.23 μM), the drug of choice against this parasite. An evaluation of cytotoxicity using VERO cells showed that compound 1 was less cytotoxic than metronidazole (CC₅₀ = 685.98 vs. CC₅₀ = 68 μM, respectively), with a favorable selectivity index (SI = 879). In vivo, we found that 97.2 % of parasite load was eliminated after intragastric administration of compound 1 (75 mg/kg). An analysis of the oral pharmacokinetic profile revealed a double peak of maximum concentration. Pharmacokinetic parameters indicated an absolute bioavailability approaching 33 %, a prolonged half-life, a large distribution volume, and slow clearance. This pharmacokinetic behavior of compound 1 makes it a promising candidate for the treatment of infections caused by both intestinal and systemic parasites.     

Hepatotoxicity of l,3,5-Trinitro-2-acetyl pyrrole derived from nitrosation of Maillard reaction product in BALB/C mouse

1,3,5-Trinitro-2-acetyl pyrrole (TNAP) is a product derived from the reaction of 2-acetyl pyrrole with nitrite in the model of Maillard browning systems. This compound is moderately mutagenic to the Salmonella strains TA98 and TA100 and is markedly cytotoxic to mouse C3H10T1/2 cells. Experiments are performed to investigate the effects of TNAP on the hepatic toxicity in mouse. Male BALB/C mice were subjected to a dose of 7.2 mg/kg body weight twice a week by i.p. injection for 24 weeks, then followed by a feeding diet for 21 weeks. TNAP-treated mice showed an increase in mortality and time-dependent appearance of lesions in the liver. TNAP is hepatotoxic as demonstrated by a marked increase in the activities of serum alanine transaminase (ALT) and aspartic transaminase (AST). TNAP-related lesions observed histologically in mice, included hapatic atrophy, mild fatty metamorphosis with multilocular cysts in the liver. In conclusion, TNAP was considered to be a toxic compound in mice as evidenced by increased incidences of mortality, and lesions of liver.     

Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2

To improve the metabolic stability profile of BMS-741672 (1a), we undertook a structure–activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of 2d (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate 1a, the tert-butyl amine 2d showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability. Furthermore, compound 2d exhibited improved affinity for CCR5 and good activity in models of both monocyte migration and multiple sclerosis in the hCCR2 knock-in mouse. The synthesis of 2d was facilitated by the development of a simplified approach to key intermediate (4R)-9b that deployed a stereoselective reductive amination which may prove to be of general interest.     

Discovery of the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer

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Discovery of PEGylated 6-Benzhydryl-4-amino-quinazolines as Peripherally Restricted CB1R Inverse Agonists

The 6-benzhydryl-4-amino-quinolin-2-ones are peripherally restricted CB₁ receptor inverse agonists (CB₁RIAs) that have been reported to attenuate obesity and improve insulin sensitivity in the diet-induced obese (DIO) mouse model. However, chronic dosing of select compounds from the series showed time-dependent brain accumulation despite a low brain/plasma exposure ratio. To address this issue, a PEGylation approach was employed to identify a novel series of homodimeric 6-benzhydryl-4-amino-quinazoline–PEG conjugates with an extended half-life. The lead compound 18 engaged peripheral CB₁Rs in a gastrointestinal (GI) tract motility study and demonstrated a high level of peripheral restriction in a chronic DIO mouse pharmacokinetic study.     

Synthesis and Evaluation of the Metabolites of AMG 221, a Clinical Candidate for the Treatment of Type 2 Diabetes

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