RESUMO
Ampakine compounds have been shown to reverse opiate-induced respiratory depression by activation of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. However, their pharmacological exploitations are hindered by low blood-brain barrier (BBB) permeability and limited brain distribution. Here, we explored whether thiamine disulfide prodrugs with the ability of "lock-in" can be used to solve these problems. A series of thiamine disulfide prodrugs 7a-7f of ampakine compound LCX001 was synthesized and evaluated. The trials in vitro showed that prodrugs 7e, 7d, 7f possessed a certain stability in plasma and quickly decomposed in brain homogenate by the disulfide reductase. In vivo, prodrug 7e decreased the peripheral distribution of LCX001 and significantly increased brain distribution of LCX001 after i.v. administration. This compound showed 2.23- and 3.29-fold greater increases in the AUC0-t and MRT0-t of LCX001 in brain, respectively, than did LCX001 itself. A preliminary pharmacodynamic study indicated that the required molar dose of prodrug 7e was only one eighth that of LCX001 required to achieve the same effect in mice. These findings provide an important reference to evaluate the clinical outlook of ampakine compounds.
Assuntos
Depressão/tratamento farmacológico , Oxidiazóis/administração & dosagem , Pró-Fármacos/administração & dosagem , Tiamina/análogos & derivados , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Depressão/induzido quimicamente , Depressão/patologia , Camundongos , Alcaloides Opiáceos/toxicidade , Pró-Fármacos/síntese química , Receptores de AMPA/metabolismo , Receptores de Glutamato/metabolismo , Tiamina/administração & dosagem , Tiamina/síntese química , Distribuição TecidualRESUMO
In order to investigate trelagliptin succinate's stability in solution, recrystallization and suspension methods in polar solvent (mainly in water and 95% alcohol) were used to study the crystal form transformation of trelagliptin succinate. Single crystal X-ray diffraction, powder X-ray diffraction and thermalgravimetric analysis, and differential scanning calorimetry were used to characterize the structure of the solid state form before and after transformation. The results showed that trelagliptin succinate can easily convert to trelagliptin hemi-succinate mediated by solvent, especially by polar solvent, namely trelagliptin hemi-succinate is more stable than trelagliptin succinate in solution.
Assuntos
Ácido Succínico/química , Uracila/análogos & derivados , Varredura Diferencial de Calorimetria , Cristalização , Cristalografia por Raios X , Estabilidade de Medicamentos , Pós , Solventes , Uracila/química , Água , Difração de Raios XRESUMO
Herein, we described a new class of uncharged non-pyridinium reactivators for nerve agent-inhibited acetylcholinesterase (AChE). Based on a dual site binding strategy, we conjugated the imidazolium aldoxime to different peripheral site ligands (PSLs) of AChE through alkyl chains. Compared with the known quaternary pyridinium reactivators, two of the resulting conjugates (7g and 7h) were highlighted to be the first efficient non-pyridinium oxime conjugates exhibiting similar or superior ability to reactivate sarin-, VX- and tabun-inhibited AChE. Moreover, they were more broad-spectrum reactivators.
Assuntos
Acetilcolinesterase/metabolismo , Substâncias para a Guerra Química/química , Reativadores da Colinesterase/química , Oximas/química , Acetilcolinesterase/química , Sítios de Ligação , Reativadores da Colinesterase/síntese química , Reativadores da Colinesterase/metabolismo , Humanos , Imidazóis/química , Cinética , Ligantes , Simulação de Acoplamento Molecular , Oximas/síntese química , Oximas/metabolismo , Ligação Proteica , Estrutura Terciária de ProteínaRESUMO
We have developed a series of substituted 4-(thiophen-2-ylmethyl)-2H-phthalazin-1-ones as potent PARP-1 inhibitors. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to, or higher than AZD-2281. Among these compounds, 18q appeared to be the most notable one, which displayed an 8-fold improvement in enzymatic activity compared to AZD-2281. These efforts lay the foundation for our further investigation.
Assuntos
Inibidores Enzimáticos/farmacologia , Ftalazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Tiofenos/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Ftalazinas/síntese química , Ftalazinas/química , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/químicaRESUMO
BACKGROUND: Portal vein thrombosis (PVT) is a condition caused by hemodynamic disorders. It may be noted in the portal vein system when there is an inflammatory stimulus in the abdominal cavity. However, PVT is rarely reported after hepatectomy. At present, related guidelines and major expert opinions tend to consider vitamin K antagonists or low-molecular weight heparin (LMWH) as the standard treatment. But based on research, direct oral anticoagulants may be more effective and safe for noncirrhotic PVT and are also beneficial by reducing the recurrence rate of PVT. CASE SUMMARY: A 51-year-old woman without any history of disease felt discomfort in her right upper abdomen for 20 d, with worsening for 7 d. Contrast-enhanced computed tomography (CECT) of the upper abdomen showed right liver intrahepatic cholangiocarcinoma with multiple intrahepatic metastases but not to the left liver. Therefore, she underwent right hepatic and caudate lobectomy. One week after surgery, the patient underwent a CECT scan, due to nausea, vomiting, and abdominal distension. Thrombosis in the left branch and main trunk of the portal vein and near the confluence of the splenic vein was found. After using LMWH for 22 d, CECT showed no filling defect in the portal vein system. CONCLUSION: Although PVT after hepatectomy is rare, it needs to be prevented during the perioperative period.
RESUMO
Morinda officinalis oligosaccharides (MOO) are an oral drug approved in China for the treatment of depression in China. However, MOO is hardly absorbed so that their anti-depressant mechanism has not been elucidated. Here, we show that oral MOO acted on tryptophan â 5-hydroxytryptophan (5-HTP) â serotonin (5-HT) metabolic pathway in the gut microbiota. MOO could increase tryptophan hydroxylase levels in the gut microbiota which accelerated 5-HTP production from tryptophan; meanwhile, MOO inhibited 5-hydroxytryptophan decarboxylase activity, thus reduced 5-HT generation, and accumulated 5-HTP. The raised 5-HTP from the gut microbiota was absorbed to the blood, and then passed across the blood-brain barrier to improve 5-HT levels in the brain. Additionally, pentasaccharide, as one of the main components in MOO, exerted the significant anti-depressant effect through a mechanism identical to that of MOO. This study reveals for the first time that MOO can alleviate depression via increasing 5-HTP in the gut microbiota.
RESUMO
Cancer stem cells (CSCs) are reported to play essential roles in chemoresistance and metastasis. Pathways regulating CSC self-renewal and proliferation, such as Hedgehog, Notch, Wnt/ß-catenin, TGF-ß, and Myc, may be potential therapeutic targets. Here, a functional screening from the focused library with 365 compounds is performed by a step-by-step strategy. Among these candidate molecules, phenyl-2-pyrimidinyl ketone 4-allyl-3-amino selenourea (CU27) is chosen for further identification because it proves to be the most effective compound over others on CSC inhibition. Through ingenuity pathway analysis, it is shown CU27 may inhibit CSC through a well-known stemness-related transcription factor c-Myc. Gene set enrichment analysis, dual-luciferase reporter assays, expression levels of typical c-Myc targets, molecular docking, surface plasmon resonance, immunoprecipitation, and chromatin immunoprecipitation are conducted. These results together suggest CU27 binds c-Myc bHLH/LZ domains, inhibits c-Myc-Max complex formation, and prevents its occupancy on target gene promoters. In mouse models, CU27 significantly sensitizes sorafenib-resistant tumor to sorafenib, reduces the primary tumor size, and inhibits CSC generation, showing a dramatic anti-metastasis potential. Taken together, CU27 exerts inhibitory effects on CSC and CSC-associated traits in hepatocellular carcinoma (HCC) via c-Myc transcription activity inhibition. CU27 may be a promising therapeutic to treat sorafenib-resistant HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Compostos de Selênio , Selênio , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Detecção Precoce de Câncer , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Camundongos , Simulação de Acoplamento Molecular , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Selênio/metabolismo , Selênio/farmacologia , Compostos de Selênio/metabolismo , Compostos de Selênio/farmacologia , Sorafenibe/metabolismo , Sorafenibe/farmacologiaRESUMO
We report herein the design and synthesis of novel 1-[3-(dimethylamino)propyl]indolin-2-one derivatives based on the structural features of Sunitinib, a known multitargeted receptor tyrosine kinase inhibitor, and TMP-20, a previously discovered compound with good antitumor activity in our lab. These newly synthesized derivatives were evaluated for in vitro activity against five human cancer cell lines and VEGF/bFGF-stimulated HUVECs. Results revealed that all of the target compounds 1a-p show potent antitumor activity, compounds 1e-h (IC(50)'s: 0.45-5.08 µM) are more active than Sunitinib (IC(50)'s: 1.35-6.61 µM), and the most active compound 1 h (IC(50): 0.47-3.11 µM) is 2.1-4.6-fold more potent than Sunitinib against all five cancer cell lines. In addition, like Sunitinib, 1a-p have higher selectivity on VEGF-stimulated HUVEC other than bFGF-stimulated HUVEC.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Amidas/química , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Halogênios/química , Humanos , Indóis/química , Concentração Inibidora 50 , Estrutura Molecular , Pirróis/química , SunitinibeRESUMO
Human rhinovirus (HRV) is the most important etiologic agent causing common colds. No effective anti-HRV agents are currently available. In this paper we describe the synthesis and the evaluation of novel chloropyridazine derivatives (compounds 5a-g) as potent human rhinovirus (HRV) capsid-binding inhibitors. Results showed that compound 5e and 5f exhibited effective anti-HRV activity against HRV-2 and HRV-14. In addition, compound 5e and 5f showed lower cytotoxicity than Pirodavir.
Assuntos
Antivirais/síntese química , Proteínas do Capsídeo/antagonistas & inibidores , Piridazinas/síntese química , Rhinovirus/efeitos dos fármacos , Antivirais/farmacologia , Resfriado Comum/tratamento farmacológico , Humanos , Piridazinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Analgesics and sedative hypnotics in clinical use often give rise to significant side effects, particularly respiratory depression. For emergency use, specific antagonists are currently administered to counteract respiratory depression. However, antagonists are often short-lasting and eliminate drug generated analgesia. To resolve this issue, novel positive AMPA modulators, LCX001, was tested to alleviate respiratory depression triggered by different drugs. The acetic acid writhing and hot-plate test were conducted to evaluate analgesic effect of LCX001. Binding assay, whole-cell recording, live cell imaging, and Ca2+ imaging were used to clarify mechanism and impact of LCX001 on respiratory protection. Results showed that LCX001 effectively rescued and prevented opioid (fentanyl and TH-030418), propofol, and pentobarbital-induced respiratory depression by strengthening respiratory frequency and minute ventilation. The acetic acid writhing test and hot-plate test revealed potent anti-nociceptive efficacy of LCX001, in contrast to other typical ampakines that did not affect analgesia. Furthermore, LCX001 potentiated [3H]AMPA and L-glutamate binding affinity to AMPA receptors, and facilitated glutamate-evoked inward currents in HEK293 cells stably expressing GluA2(R). LCX001 had a typical positive modulatory impact on AMPAR-mediated function. Importantly, application of LCX001 generated a significant increase in GluA2(R) surface expression, and restrained opioid-induced abnormal intracellular Ca2+ load, which might participate in breathing modulation. Our study improves therapeutic interventions for the treatment of drug induced respiratory depression, and increases understanding of potential mechanism of AMPA receptor modulators.
RESUMO
Ivabradine hydrochloride (IVA-HCl) (systematic name: {[3,4-dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl]methyl}[3-(7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)propyl]methylazanium), is a novel medication used for the symptomatic management of stable angina pectoris. In many recent patents, it has been claimed to exist in a very large number of polymorphic, hydrated and solvated phases, although no detailed analysis of the structural features of these forms has been published to date. Here, we have successfully crystallized the tetrahydrate form of IVA-HCl (form ß), C27H37N2O5+·Cl-·4H2O, and elucidated its structure for the first time. Simultaneously, a new crystal form of IVA-HCl, i.e. the hemihydrate (form II), C27H37N2O5+·Cl-·0.5H2O, was discovered. Its crystal structure was also accurately determined and compared to that of the tetrahydrate form. While the tetrahydrate form of IVA-HCl crystallized in the orthorhombic space group P212121, the new form (hemihydrate) was solved in the monoclinic space group P21. Detailed conformational and packing comparisons between the two forms have allowed us to understand the role of water in the crystal assembly of this hydrochloride salt. The stabilities of the two forms were compared theoretically by calculating the binding energy of the water in the crystal lattice using differential scanning calorimetry (DSC). The stability experiments show that the tetrahydrate is stable under high-humidity conditions, while the hemihydrate is stable under high-temperature conditions.
Assuntos
Fármacos Cardiovasculares/química , Ivabradina/química , Varredura Diferencial de Calorimetria , Estabilidade de Medicamentos , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Termodinâmica , Água/química , Difração de Raios XRESUMO
Cisapride monohydrate (systematic name: 4-amino-5-chloro-N-{(3RS,4SR)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl}-2-methoxybenzamide monohydrate), C23H29ClFN3O4·H2O, is a nondopamine-blocking gastrokinetic drug. A new polymorph of cisapride monohydrate has been reported nearly three decades after the report of its first known crystal structure [Collin et al. (1989). J. Mol. Struct. 214, 159-175]. The second polymorph is also monoclinic, but with different unit-cell parameters. A comparison of both polymorphic forms shows that the difference is thus not in the molecular conformation but in the arrangements of molecules in the crystal packing. The crystal morphology of two forms was predicted with the BFDH model in Materials Studio and inferred that the powder of the new polymorph has better flowability than the original polymorph. The results of DSC (differential scanning calorimetry) analysis and slurry experiments show that both polymorphs are stable at room temperature.
Assuntos
Cisaprida/química , Cisaprida/farmacocinética , Varredura Diferencial de Calorimetria , Cristalografia por Raios X , Ligação de Hidrogênio , Conformação MolecularRESUMO
The use of opioid drugs for pain relief can induce life-threatening respiratory depression. Although naloxone effectively counteracts opioid-induced respiratory depression, it diminishes the efficacy of analgesia. Our studies indicate that ampakines, in particular, a brain-targeted compound XD-8-17C, are able to reverse respiratory depression without affecting analgesia at relatively low doses. Mice and rats were subcutaneously or intravenously injected with the opioid agonist TH-030418 to induce moderate or severe respiratory depression. XD-8-17C was intravenously administered before or after TH-030418. The effect of XD-8-17C on opioid-induced respiratory depression was evaluated in terms of the opioid-induced acute death rate, arterial blood gas analysis and pulmonary function tests. In addition, the hot-plate test was conducted to investigate whether XD-8-17C influenced opioid-induced analgesia. Pre-treatment with XD-8-17C significantly reduced opioid-induced acute death, and increased the median lethal dose of TH-030418 by 4.7-fold. Blood gas analysis and pulmonary function tests demonstrated that post-treatment with XD-8-17C alleviated respiratory depression, as indicated by restoration of arterial blood gas (pO2, sO2, cK+) and lung function parameters (respiratory frequency, minute ventilation) to the normal range. The hot-plate test showed that XD-8-17C had no impact on the antinociceptive efficacy of morphine. The ability of XD-8-17C to reverse opioid-induced respiratory depression has the potential to increase the safety and convenience of opioid treatment. These findings contribute to the discovery of novel therapeutic agents that protect against opioid-induced respiratory depression without loss of analgesia.
Assuntos
Analgésicos Opioides/efeitos adversos , Encéfalo/efeitos dos fármacos , Oxidiazóis/farmacologia , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/tratamento farmacológico , Animais , Gasometria , Encéfalo/metabolismo , Feminino , Masculino , Camundongos , Oxidiazóis/uso terapêutico , Ratos , Insuficiência Respiratória/sangueRESUMO
Regorafenib {systematic name: 4-[4-({[4-chloro-3-(trifluoromethy)phenyl]carbamoyl}amino)-3-fluorophenoxy]-1-methylpyridine-2-carboxamide}, C21H15ClF4N4O3, is a potent anticancer and anti-angiogenic agent that possesses various activities on the VEGFR, PDGFR, raf and/or flt-3 kinase signaling molecules. The compound has been crystallized as polymorphic form I and as the monohydrate, C21H15ClF4N4O3·H2O. The regorafenib molecule consists of biarylurea and pyridine-2-carboxamide units linked by an ether group. A comparison of both forms shows that they differ in the relative orientation of the biarylurea and pyridine-2-carboxamide units, due to different rotations around the ether group, as measured by the C-O-C bond angles [119.5â (3)° in regorafenib and 116.10â (15)° in the monohydrate]. Meanwhile, the conformational differences are reflected in different hydrogen-bond networks. Polymorphic form I contains two intermolecular N-H...O hydrogen bonds, which link the regorafenib molecules into an infinite molecular chain along the b axis. In the monohydrate, the presence of the solvent water molecule results in more abundant hydrogen bonds. The water molecules act as donors and acceptors, forming N-H...O and O-H...O hydrogen-bond interactions. Thus, R4(2)(28) ring motifs are formed, which are fused to form continuous spiral ring motifs along the a axis. The (trifluoromethyl)phenyl rings protrude on the outside of these motifs and interdigitate with those of adjacent ring motifs, thereby forming columns populated by halogen atoms.
Assuntos
Inibidores da Angiogênese/química , Antineoplásicos/química , Compostos de Fenilureia/química , Piridinas/química , Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Cristalografia por Raios X , Ligação de Hidrogênio , Estrutura Molecular , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Solventes/químicaRESUMO
Early studies with first-generation poly (ADP-ribose) polymerase (PARP) inhibitors have already indicated some therapeutic potential for sulfur mustard (SM) injuries. The available novel and more potential PARP inhibitors, which are undergoing clinical trials as drugs for cancer treatment, bring it back to the centre of interest. However, the role of PARP-1 in SM-induced injury is not fully understood. In this study, we selected a high potent specific PARP inhibitor ABT-888 as an example to investigate the effect of PARP inhibitor in SM injury. The results showed that in both the mouse ear vesicant model (MEVM) and HaCaT cell model, PARP inhibitor ABT-888 can reduce cell damage induced by severe SM injury. ABT-888 significantly reduced SM induced edema and epidermal necrosis in MEVM. In the HaCaT cell model, ABT-888 can reduce SM-induced NAD(+)/ATP depletion and apoptosis/necrosis. Then, we studied the mechanism of PARP-1 in SM injury by knockdown of PARP-1 in HaCaT cells. Knockdown of PARP-1 protected cell viability and downregulated the apoptosis checkpoints, including p-JNK, p-p53, Caspase 9, Caspase 8, c-PARP and Caspase 3 following SM-induced injury. Furthermore, the activation of AKT can inhibit autophagy via the regulation of mTOR. Our results showed that SM exposure could significantly inhibit the activation of Akt/mTOR pathway. Knockdown of PARP-1 reversed the SM-induced suppression of the Akt/mTOR pathway. In summary, the results of our study indicated that the protective effects of downregulation of PARP-1 in SM injury may be due to the regulation of apoptosis, necrosis, energy crisis and autophagy. However, it should be noticed that PARP inhibitor ABT-888 further enhanced the phosphorylation of H2AX (S139) after SM exposure, which indicated that we should be very careful in the application of PARP inhibitors in SM injury treatment because of the enhancement of DNA damage.
RESUMO
Soman is a highly toxic nerve agent with strong inhibition of acetylcholinesterase (AChE), but of the few reactivators showing antidotal efficiency for soman-inhibited AChE presently are all permanently charged cationic oximes with poor penetration of the blood-brain barrier. To overcome this problem, uncharged reactivators have been designed and synthesized, but few of them were efficient for treating soman poisoning. Herein, we used a dual site biding strategy to develop more efficient uncharged reactivators. The ortho-hydroxylbenzaldoximes were chosen as reactivation ligands of AChE to prevent the secondary poisoning of AChE, and simple aromatic groups were used as peripheral site ligands of AChE, which were linked to the oximes in a similar way as that found in the reactivator HI-6. The in vitro experiment demonstrated that some of the resulting conjugates have robust activity against soman-inhibited AChE, and oxime 8b was highlighted as the most efficient one. Although not good as HI-6 in vitro, these new compounds hold promise for development of more efficient centrally acting reactivators for soman poisoning due to their novel nonquaternary structures, which are predicted to be able to cross the blood-brain barrier.
Assuntos
Inibidores da Colinesterase/intoxicação , Reativadores da Colinesterase/farmacologia , Soman/intoxicação , Barreira Hematoencefálica , Reativadores da Colinesterase/síntese química , Humanos , Oximas/farmacocinética , Oximas/farmacologia , Compostos de Piridínio/farmacocinética , Compostos de Piridínio/farmacologiaAssuntos
Fenofibrato/farmacologia , Resistência à Insulina , Síndrome Metabólica , Tiazolidinedionas/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Sinergismo Farmacológico , Ingestão de Alimentos/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Lipídeos/sangue , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Fígado/efeitos dos fármacos , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Camundongos , Camundongos Endogâmicos ICR , RNA Mensageiro/metabolismo , Rosiglitazona , Glutamato de SódioRESUMO
Vortioxetine, C18H22N2S, (1), systematic name 1-{2-[(2,4-di-methyl-phen-yl)sulfan-yl]phen-yl}piperazine, a new drug used to treat patients with major depressive disorder, has been crystallized as the free base and its methanol monosolvate, C18H22N2S·CH3OH, (2). In both structures, the vortioxetine mol-ecules have similar conformations: in (1), the dihedral angle between the aromatic rings is 80.04â (16)° and in (2) it is 84.94â (13)°. The C-S-C bond angle in (1) is 102.76â (14)° and the corresponding angle in (2) is 103.41â (11)°. The piperazine ring adopts a chair conformation with the exocyclic N-C bond in a pseudo-equatorial orientation in both structures. No directional inter-actions beyond normal van der Waals contacts could be identified in the crystal of (1), whereas in (2), the vortioxetine and methanol mol-ecules are linked by N-Hâ¯O and O-Hâ¯N hydrogen bonds, generating [001] chains.
RESUMO
It has been universally acknowledged that the increase in cardiac and vascular stiffness is due to the formation of advanced glycosylation end-products (AGEs). Research on the stable form of 3-(carboxymethyl)-4-methylthiazol bromide sodium salt (C6H7BrNNaO2S) showed that it had a notable effect on breaking the AGEs. Two compounds with novel structures, zwitterionic 3-(carboxymethyl)-4-methylthiazol (C6H7O2NS) and a dipolymer (C12H15O4N2S2Br) complex, were obtained. When compared with the forms of sodium salt and dipolymer, zwitterion had an obvious advantage in stability, solubility, synthesis and pH, which made the zwitterion a promising drug. The structure of sodium salt, dipolymer and zwitterion was comparatively analyzed by such methods as single crystal X-ray diffraction, ESI-MS, 1H NMR, FT-IR and in situ IR.
Assuntos
Produtos Finais de Glicação Avançada/química , Tiazóis/química , Cristalografia por Raios X , Detergentes/química , Detergentes/farmacologia , Estabilidade de Medicamentos , Produtos Finais de Glicação Avançada/efeitos dos fármacos , Estrutura Molecular , Solubilidade , Tiazóis/síntese química , Tiazóis/farmacologiaRESUMO
BACKGROUND AND PURPOSE: Peroxisome proliferator-activated receptors (PPARs) are attractive targets for the treatment of type 2 diabetes and the metabolic syndrome. P633H (2-[4-(2-Fluoro-benzenesulphonyl)-piperazin-1-yl]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid), a novel PPARalpha/gamma dual agonist, was investigated for its very different effects on insulin resistance and dyslipidemia in db/db and KK-A(y) mice. EXPERIMENTAL APPROACH: The action of P633H at PPARalpha/gamma was characterized by using transactivation assays. Functional activation of PPARalpha/gammain vitro was confirmed by pre-adipocyte differentiation and regulation of target gene expression. Anti-diabetic studies were performed in two different diabetic mice models in vivo. KEY RESULTS: P633H activated both PPARalpha and PPAR gamma, (with EC(50) values of 0.012 micromol and 0.032 micromol respectively). Additionally, P633H promoted pre-adipocyte differentiation, up-regulated expression of adipose specific transport protein (aP2) mRNA (3T3-Ll cells) and acyl-CoA oxidase mRNA (LO2 cells). In db/db mice, P633H reduced serum glucose, insulin, triglycerides, non-esterified fatty acids and liver triglycerides. It also improved glucose intolerance without affecting food intake and body weight after 15 days of treatment. However in KK-A(y) mice, hyperglycaemia, dyslipidemia and impaired glucose tolerance were not relieved even after a 25 day treatment with P633H. Further studies with real-time PCR and electron microscopy revealed that P633H promoted progression of diabetes in KK-A(y) mice by increasing hepatic gluconeogenesis and exacerbating pancreatic pathology. CONCLUSION AND IMPLICATIONS: Although P633H was a high-potency PPARalpha/gamma dual agonist, with good functional activity in vitro, it produced opposing anti-diabetic effects in db/db and KK-A(y) mice.