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Metabolic Stability (metabolic + stability)
Selected AbstractsNew Tetrahydrobenzindoles as Potent and Selective 5-HT7 Antagonists with Increased in vitro Metabolic StabilityCHEMINFORM, Issue 23 2003Chika Kikuchi Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: New Diarylmethylpiperazines as Potent and Selective Nonpeptidic ,-Opioid Receptor Agonists with Increased in vitro Metabolic Stability.CHEMINFORM, Issue 10 2001Niklas Plobeck Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Strength of C,H Bonds at Nitrogen , -Position:Implication for Metabolic Stability of Nitrogen-containing Drug MoleculesCHINESE JOURNAL OF CHEMISTRY, Issue 4 2008Xiang-Ming MENG Abstract The available experimental ,C-H BDEs of a variety of amine-containing molecules were examined by using the G3B3 and CBS-Q methods. The verified values were employed to benchmark and calibrate the density functional theory methods. It was found that the (U)BHandH/6-311++G(2df, 2p)//(U)B3LYP/6-31G(d) method was a fast and accurate method for calculating C,H BDEs at nitrogen , -positions. By using the newly benchmarked BHandH method, the ,C,H BDEs in a number of nitrogen-containing drug molecules were calculated, where a dramatic variation of the ,C,H BDEs was discovered. To understand this variation, the effects of mono- and double-substitution at both carbon and nitrogen atoms on the ,C-H BDEs were systematically studied. The origin of the substitution effects was thoroughly discussed in terms of four categories of substituents. [source] The sequential syntheses of [76Br]FBAU 3,,5,-dibenzoate and [76Br]FBAUJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 13 2001Chih-Hao K. Kao Abstract Thymidine analogs labeled with positron emitting radionuclides are potential proliferation markers for positron emission tomography (PET). Bromine-76 (T1/2=16.2 h) is our choice of radionuclide, because it allows for maximal DNA incorporation of the tracer. Following the literature descriptions, 76Br was produced using the 75As (3He, 2n) 76Br reaction. We then recovered 76Br from the target in the form of [76Br]NH4Br with a yield of 60±12% (n=32). Peracetic acid was used as the oxidant for electrophilic bromodestannylation to prepare [76Br]FBAU 3,,5,-dibenzoate (71.2±12.1%, RCY) and a basic hydrolysis of the dibenzoate then yielded [76Br]FBAU. The yield of the hydrolysis reaction was 53.1±9.2% when heated at 100°C for 15 min or quantitative (decay corrected) when left at room temperature overnight. The sequential synthesis of [76Br]FBAU 3,,5,-dibenzoate and [76Br]FBAU allowed us to perform a side-by-side comparison of their metabolic stabilities. While [76Br]FBAU 3,,5,-dibenzoate was hydrolyzed to [76Br]FBAU within 10 minutes by hepatocyte at 37°C, [76Br]FBAU was stable and no [76Br]Br, was released from either radiopharmaceutical. Both compounds are potential proliferation markers for PET. Copyright © 2001 John Wiley & Sons, Ltd. [source] Preparation of 4-[11C]methylmetaraminol, a potential PET tracer for assessment of myocardial sympathetic innervationJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 1 2003Oliver Langer Abstract The false adrenergic neurotransmitter [11C]meta -hydroxyephedrine ([11C]HED) is currently the PET tracer of choice for assessment of myocardial sympathetic innervation. The molecule is metabolised in the 4-position of the aromatic ring. The resulting radiolabelled metabolites need to be measured in order to obtain an arterial input function. Our aim was the development of a PET tracer with an increased metabolic stability relative to [11C]HED. We selected 4-methylmetaraminol as a candidate molecule for radiolabelling with 11C (t1/2 20.4 min). Our radiosynthetic approach towards 4-[11C]methylmetaraminol involved a palladium-catalyzed cross-coupling reaction of a protected 4-trimethylstannyl derivative of metaraminol with [11C]methyl iodide followed by removal of the protective groups. 4-[11C]methylmetaraminol was obtained in a final decay-corrected radiochemical yield of 20,25% within a synthesis time of 60,80 min. The specific radioactivity at the end of the synthesis ranged from 18,37 to GBq/,mol. The unlabelled reference molecule, 4-methylmetaraminol, was prepared in a 5-step synthesis starting from metaraminol. A biological evaluation of 4-[11C]methylmetaraminol is in progress and the results will be reported elsewhere. Copyright © 2002 John Wiley & Sons, Ltd. [source] Introduction of lipidization,cationization motifs affords systemically bioavailable neuropeptide Y and neurotensin analogs with anticonvulsant activitiesJOURNAL OF PEPTIDE SCIENCE, Issue 9 2010Brad R. Green Abstract The neuropeptides galanin (GAL), neuropeptide Y (NPY) or neurotensin (NT) exhibit anticonvulsant activities mediated by their respective receptors in the brain. To transform these peptides into potential neurotherapeutics, their systemic bioavailability and metabolic stability must be improved. Our recent studies with GAL analogs suggested that an introduction of lipoamino acids in the context of oligo-Lys residues (lipidization,cationization motif) significantly increases their penetration into the brain, yielding potent antiepileptic compounds. Here, we describe an extension of this strategy to NPY and NT. Rationally designed analogs of NPY and NT containing the lipidization,cationization motif were chemically synthesized and their physicochemical and pharmacological properties were characterized. The analogs NPY-BBB2 and NT-BBB1 exhibited increased serum stability, possessed log D > 1.1, retained high affinities toward their native receptors and produced potent antiseizure activities in animal models of epilepsy following intraperitoneal administration. Our results suggest that the combination of lipidization and cationization may be an effective strategy for improving systemic bioavailability and metabolic stability of various neuroactive peptides. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd. [source] Feasibility study of aerosolized prostaglandin E1 microspheres as a noninvasive therapy for pulmonary arterial hypertensionJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2010Vivek Gupta Abstract This study was designed to test the feasibility of polymeric microspheres as an inhalable carrier for prostaglandin E1 (PGE1) for treatment of pulmonary arterial hypertension. Poly(lactic- co -glycolic acid) (PLGA) microspheres were prepared by a double emulsion,solvent evaporation method. Six different microspheric formulations were prepared using two different blends of PLGA (50:50 and 85:15) and varying concentrations of polyvinyl alcohol (PVA) in the external aqueous phase (EAP). The particles were characterized for morphology, size, aerodynamic diameter, entrapment efficiency, release patterns, and metabolic stability. Pulmonary absorption was studied in a rat model, and safety of the formulations was evaluated by measuring cytotoxicity in Calu-3 cells and assessing injury markers in bronchoalveolar lavage (BAL) fluid. Both actual particle size and aerodynamic diameter of the formulations decreased with increasing PVA concentration. The mass median aerodynamic diameter of the particles was within the respirable range. Entrapment efficiency increased with increasing PVA concentration; PLGA 85:15 showed better entrapment due to hydrophobic interactions with the drug. Compared to intravenously administered PGE1, microspheres prepared with PLGA 85:15 produced a 160-fold increase in the half-life of PGE1 following pulmonary administration. Although plain PGE1 showed rapid degradation in rat lung homogenate, PGE1 entrapped in the particles remained intact for about 8,h. Optimized formulations were demonstrated to be safe, based on analysis of cytotoxicity and lung-injury markers in BAL fluid. Overall, the data suggest that microspheric PGE1 formulations have the potential to be used as a noninvasive and controlled-release alternative to the current medications used for treatment of pulmonary arterial hypertension that are administered by continuous infusion or require multiple inhalations. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1774,1789, 2010 [source] Pharmacokinetic aspects of biotechnology productsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2004Lisa Tang Abstract In recent years, biotechnologically derived peptide and protein-based drugs have developed into mainstream therapeutic agents. Peptide and protein drugs now constitute a substantial portion of the compounds under preclinical and clinical development in the global pharmaceutical industry. Pharmacokinetic and exposure/response evaluations for peptide and protein therapeutics are frequently complicated by their similarity to endogenous peptides and proteins as well as protein nutrients. The first challenge frequently comes from a lack of sophistication in various analytical techniques for the quantification of peptide and protein drugs in biological matrices. However, advancements in bioassays and immunoassays,along with a newer generation of mass spectrometry-based techniques,can often provide capabilities for both efficient and reliable detection. Selection of the most appropriate route of administration for biotech drugs requires comprehensive knowledge of their absorption characteristics beyond physicochemical properties, including chemical and metabolic stability at the absorption site, immunoreactivity, passage through biomembranes, and active uptake and exsorption processes. Various distribution properties dictate whether peptide and protein therapeutics can reach optimum target site exposure to exert the intended pharmacological response. This poses a potential problem, especially for large protein drugs, with their typically limited distribution space. Binding phenomena and receptor-mediated cellular uptake may further complicate this issue. Elimination processes,a critical determinant for the drug's systemic exposure,may follow a combination of numerous pathways, including renal and hepatic metabolism routes as well as generalized proteolysis and receptor-mediated endocytosis. Pharmacokinetic/pharmacodynamic (PK/PD) correlations for peptide and protein-based drugs are frequently convoluted by their close interaction with endogenous substances and physiologic regulatory feedback mechanisms. Extensive use of pharmacokinetic and exposure/response concepts in all phases of drug development has in the past been identified as a crucial factor for the success of a scientifically driven, evidence-based, and thus accelerated drug development process. Thus, PK/PD concepts are likely to continue and expand their role as a fundamental factor in the successful development of biotechnologically derived drug products in the future. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:2184,2204, 2004 [source] Moxidectin and ivermectin metabolic stability in sheep ruminal and abomasal contentsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2005A. LIFSCHITZ The oral administration of macrocyclic lactones to sheep leads to poorer efficacy and shorter persistence of the antiparasitic activity compared to the subcutaneous treatment. Gastrointestinal biotransformation occurring after oral treatment to ruminant species has been considered as a possible cause of the differences observed between routes of administration. The current work was addressed to evaluate on a comparative basis the in vitro metabolism of moxidectin (MXD) and ivermectin (IVM) in sheep ruminal and abomasal contents. Both compounds were incubated under anaerobic conditions during 2, 6 and 24 h in ruminal and abomasal contents collected from untreated adult sheep. Drug concentrations were measured by high-performance liquid chromatography with fluorescence detection after sample clean up and solid phase extraction. Neither MXD nor IVM suffered metabolic conversion and/or chemical degradation after 24-h incubation in ruminal and abomasal contents collected from adult sheep. Unchanged MXD and IVM parent compounds represented between 95.5 and 100% of the total drug recovered in the ruminal and abomasal incubation mixtures compared with those measured in inactive control incubations. The partition of both molecules between the solid and fluid phases of both sheep digestive contents was assessed. MXD and IVM were extensively bound (>90%) to the solid material of both ruminal and abomasal contents collected from sheep fed on lucerne hay. The results reported here confirm the extensive degree of association to the solid digestive material and demonstrates a high chemical stability without evident metabolism and/or degradation for both MXD and IVM in ruminal and abomasal contents. [source] Functional and morphological comparison of three primary liver cell types cultured in the AMC bioartificial liverLIVER TRANSPLANTATION, Issue 4 2007Paul P.C. Poyck The selection of a cell type for bioartificial liver (BAL) systems for the treatment of patients with acute liver failure is in part determined by issues concerning patient safety and cell availability. Consequently, mature porcine hepatocytes (MPHs) have been widely applied in BAL systems. The success of clinical BAL application systems is, however, largely dependent on the functionality and stability of hepatocytes. Therefore, we compared herein the general metabolic and functional activities of MPHs with mature human hepatocytes (MHHs) in the Academic Medical Center (AMC)-BAL during a 7-day culture period. We also tested fetal human hepatocytes (FHHs), since their proliferation capacity is higher than MHHs and their function is increased compared to human liver cell lines. The results showed large differences between the 3 cell types. MHHs eliminated 2-fold more ammonia and produced 3-fold more urea than MPHs, whereas FHHs produced ammonia. Lidocaine elimination of FHHs was 3.5-fold higher than MPHs and 6.6-fold higher than of MHHs. Albumin production was not different between the 3 cell types. MPHs and FHHs became increasingly glycolytic, whereas MHHs remained metabolically stable during the whole culture period. MHHs and MPHs formed tissue-like structures inside the AMC-BAL. In conclusion, we propose that FHHs can be considered as a suitable cell type for pharmacological studies inside a bioreactor. However, we conclude that MHHs are the preferred cell source for loading a BAL device for clinical use, because of their high ammonia eliminating capacity and metabolic stability. MPHs should be considered as the best alternative cell source for BAL application, although their phenotypic instability urges application within 1 or 2 days after loading. Liver Transpl 13:589,598, 2007. © 2007 AASLD. [source] Conformational Study of Short Peptoid Models for Future Applications as Potent Antimicrobial CompoundsMACROMOLECULAR THEORY AND SIMULATIONS, Issue 3 2007Fateh Singh Nandel Abstract Development of peptides as clinically useful drugs is limited by their poor metabolic stability and low bioavailability. Recent progresses in chemical synthesis and design have led to several strategies for producing potent mimetics. This study aims to analyze sequence/structure requirements and composition for antimicrobial peptoid designs, as use of peptoids is one of the most representative approaches to meet the goal of biomimicry. Analysis of the designs showed that for maximum activity and minimum hemolysis, the plane of the aromatic residues should be at an angle between 0 and 90,° with respect to membranes, cationic residues need not be at the terminal position, and central positions should be uniform in NIle, NLys, and NPhe residues. [source] Analytical strategies for identifying drug metabolitesMASS SPECTROMETRY REVIEWS, Issue 3 2007Chandra Prakash Abstract With the dramatic increase in the number of new chemical entities (NCEs) arising from combinatorial chemistry and modern high-throughput bioassays, novel bioanalytical techniques are required for the rapid determination of the metabolic stability and metabolites of these NCEs. Knowledge of the metabolic site(s) of the NCEs in early drug discovery is essential for selecting compounds with favorable pharmacokinetic credentials and aiding medicinal chemists in modifying metabolic "soft spots". In development, elucidation of biotransformation pathways of a drug candidate by identifying its circulatory and excretory metabolites is vitally important to understand its physiological effects. Mass spectrometry (MS) and nuclear magnetic resonance (NMR) have played an invaluable role in the structural characterization and quantification of drug metabolites. Indeed, liquid chromatography (LC) coupled with atmospheric pressure ionization (API) MS has now become the most powerful tool for the rapid detection, structure elucidation, and quantification of drug-derived material within various biological fluids. Often, however, MS alone is insufficient to identify the exact position of oxidation, to differentiate isomers, or to provide the precise structure of unusual and/or unstable metabolites. In addition, an excess of endogenous material in biological samples often suppress the ionization of drug-related material complicating metabolite identification by MS. In these cases, multiple analytical and wet chemistry techniques, such as LC-NMR, enzymatic hydrolysis, chemical derivatization, and hydrogen/deuterium-exchange (H/D-exchange) combined with MS are used to characterize the novel and isomeric metabolites of drug candidates. This review describes sample preparation and introduction strategies to minimize ion suppression by biological matrices for metabolite identification studies, the application of various LC-tandem MS (LC-MS/MS) techniques for the rapid quantification and identification of drug metabolites, and future trends in this field. © 2007 Wiley Periodicals, Inc., Mass Spec Rev [source] Role of drug metabolism in drug discovery and developmentMEDICINAL RESEARCH REVIEWS, Issue 5 2001Gondi N. Kumar Abstract Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. High metabolic lability usually leads to poor bioavailability and high clearance. Formation of active or toxic metabolites will have an impact on the pharmacological and toxicological outcomes. There is also potential for drug,drug interactions with coadministered drugs due to inhibition and/or induction of drug metabolism pathways. Hence, optimization of the metabolic liability and drug,drug interaction potential of the new chemical entities are some of the most important steps during the drug discovery process. The rate and site(s) of metabolism of new chemical entities by drug metabolizing enzymes are amenable to modulation by appropriate structural changes. Similarly, the potential for drug,drug interactions can also be minimized by appropriate structural modifications to the drug candidate. However, the optimization of the metabolic stability and drug,drug interaction potential during drug discovery stage has been largely by empirical methods and by trial and error. Recently, a lot of effort has been applied to develop predictive methods to aid the optimization process during drug discovery and development. This article reviews the role of drug metabolism in drug discovery and development. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 5, 397,411, 2001 [source] High-throughput metabolic stability studies in drug discovery by orthogonal acceleration time-of-flight (OATOF) with analogue-to-digital signal capture (ADC)RAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 12 2010David G. Temesi Screening assays capable of performing quantitative analysis on hundreds of compounds per week are used to measure metabolic stability during early drug discovery. Modern orthogonal acceleration time-of-flight (OATOF) mass spectrometers equipped with analogue-to-digital signal capture (ADC) now offer performance levels suitable for many applications normally supported by triple quadruple instruments operated in multiple reaction monitoring (MRM) mode. Herein the merits of MRM and OATOF with ADC detection are compared for more than 1000 compounds screened in rat and/or cryopreserved human hepatocytes over a period of 3 months. Statistical comparison of a structurally diverse subset indicated good agreement for the two detection methods. The overall success rate was higher using OATOF detection and data acquisition time was reduced by around 20%. Targeted metabolites of diazepam were detected in samples from a CLint determination performed at 1,µM. Data acquisition by positive and negative ion mode switching can be achieved on high-performance liquid chromatography (HPLC) peak widths as narrow as 0.2,min (at base), thus enabling a more comprehensive first pass analysis with fast HPLC gradients. Unfortunately, most existing OATOF instruments lack the software tools necessary to rapidly convert the huge amounts of raw data into quantified results. Software with functionality similar to open access triple quadrupole systems is needed for OATOF to truly compete in a high-throughput screening environment. Copyright © 2010 John Wiley & Sons, Ltd. [source] Design and Synthesis of a Focused Library of Novel Aryl- and Heteroaryl-KetopiperazidesARCHIV DER PHARMAZIE, Issue 12 2004Matthias Gerlach Abstract 1-Phenyl-4-piperazinyl-carbonyl-substituted nitrogen-containing heterocycles were discovered at Zentaris as a new class of potent, synthetic, small molecule tubulin inhibitors with strong antiproliferative activity. The lead structure of this class, D-24203, proved to be a potent inhibitor of in vivo tumor growth in different xenograft models including mammary and renal cancers. As part of our efforts in the lead optimization process to expand structural diversity as well as to optimize bioavailability parameters such as solubility and metabolic stability for these compounds, we produced and evaluated a focused library containing 320 compounds. Five new heterocyclic compound classes with comparable activity properties in the cytotoxicity and tubulin polymerization assay could be identi fied. In silico calculated bioavailability parameters for selected library members provides new compound classes with improved solubility properties. Library design, development of adequate solution phase methodology, and synthesis will be presented, as well as results of lead optimization. [source] Quantitative determination of capsaicin, a transient receptor potential channel vanilloid 1 agonist, by liquid chromatography quadrupole ion trap mass spectrometry: evaluation of in vitro metabolic stabilityBIOMEDICAL CHROMATOGRAPHY, Issue 2 2009Francis Beaudry Abstract Capsaicin is the most abundant pungent molecule present in red peppers and it is widely used for food flavoring, in pepper spray in self-defense devices and more recently in ointments for the relief of neuropathic pain. Capsaicin is a selective agonist of transient receptor potential channel, vanilloid subfamily member 1. A selective and sensitive quantitative method for the determination of capsaicin by LC-ESI/MS/MS was developed. The method consisted of a protein precipitation extraction followed by analysis using liquid chromatography electrospray quadrupole ion trap mass spectrometry. The chromatographic separation was achieved using a 100 × 2 mm C18 Waters Symmetry column combined with a gradient mobile phase composed of acetonitrile and 0.1% formic acid aqueous solution at a flow rate of 220 µL/min. The mass spectrometer was operating in full-scan MS/MS mode using two-segment analysis. An analytical range of 10,5000 ng/mL was used in the calibration curve constructed in rat plasma. The interbatch precision and accuracy observed were 6.5, 6.7, 5.3 and 101.2, 102.7, 103.5% at 50, 500 and 5000 ng/mL, respectively. An in vitro metabolic stability study was performed in rat, dog and mouse liver microsomes and the novel analytical method was adapted and used to determine intrinsic clearance of capsaicin. Results suggest very rapid degradation with T1/2 ranging from 2.3 to 4.1 min and high clearance values suggesting that drug bioavailability will be considerably reduced, consequently affecting drug response and efficacy. Copyright © 2008 John Wiley & Sons, Ltd. [source] Pharmacokinetics and systemic endocrine effects of the phyto-oestrogen 8-prenylnaringenin after single oral doses to postmenopausal womenBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2006M. Rad Aims Pre-clinical data suggest that the racemic phyto-oestrogen 8-prenylnaringenin (8-PN) may have beneficial effects in postmenopausal women and may become an alternative to classical hormone replacement therapy (HRT) treatment regimes. The aim of this study was to investigate the pharmacokinetics, endocrine effects and tolerability of chemically synthesized 8-PN in postmenopausal women. Methods The study was performed using a randomized, double-blind, placebo-controlled, dose-escalation design with three groups of eight healthy postmenopausal women. In each group six subjects received 8-PN and two subjects placebo. 8-PN was given orally in doses of 50, 250 or 750 mg. Drug concentrations in serum, urine and faeces were measured up to 48 h and follicle-stimulating hormone/luteinizing hormone (LH) concentrations up to 24 h. Results All treatments were well tolerated and associated with a low incidence of (drug unrelated) adverse events. Serum concentrations of free 8-PN showed rapid drug absorption and secondary peaks suggestive of marked enterohepatic recirculation. Independent of the treatment group, approximately 30% of the dose was recovered in excreta as free compound or conjugates over the 48-h observation period. The first Cmax and AUC0,48 h showed dose linearity with ratios of 1 : 4.5 : 13.6 (Cmax) and 1 : 5.2 : 17.1 (AUC). The750- mg dose decreased LH concentrations by 16.7% (95% confidence interval 0.5, 30.2). Conclusion Single oral doses of up to 750 mg 8-PN were well tolerated by postmenopausal women. The pharmacokinetic profile of 8-PN was characterized by rapid and probably complete enteral absorption, high metabolic stability, pronounced enterohepatic recirculation and tight dose linearity. The decrease in LH serum concentrations found after the highest dose demonstrates the ability of 8-PN to exert systemic endocrine effects in postmenopausal women. [source] The Prediction of ADMET Properties Using Structure Information RepresentationsCHEMISTRY & BIODIVERSITY, Issue 11 2005Lemont The electrotopological state and molecular connectivity indices are defined as a system for molecular-structure description, using the term Structure-Information Representation. This system is built on the depiction of a molecule as a network composed of atoms of varying valence electron counts that constitute the valence state, bonded in discrete patterns constituting an electrotopological state. The system is employed in the structure,activity analysis of two sets of ADMET data. Models are created relating hepatotoxicity and human metabolic stability. The validity of these models makes them useful for activity prediction. [source] 2-Acylaminopyridin-4-ylimidazoles as p38 MAP Kinase Inhibitors: Design, Synthesis, and Biological and Metabolic EvaluationsCHEMMEDCHEM, Issue 11 2009Katharina Ziegler Dr. Abstract Targeting cytokines has become an important focus in the treatment of many inflammatory disorders. p38 MAP kinase (MAPK) is the key enzyme in regulating the biosynthesis and release of pro-inflammatory cytokines such as IL-1, and TNF,. Inhibition of p38 MAPK results in decreased expression of these cytokines. Tri- and tetrasubstituted pyridinylimidazoles are potent inhibitors of p38 MAPK. Substitution on the pyridinyl moiety allows the design of inhibitors that show increased selectivity and activity by targeting the enzyme's hydrophobic region,II. The objective of this study was to synthesize novel 1,2,4,5-tetrasubstituted imidazole derivates and to characterize them not only for their ability to inhibit p38 MAPK and modulate cytokine release in human whole blood, but also to evaluate their metabolic stability. Biological data and metabolic studies demonstrate that the introduction of a 2-acylamino function at C2 of the pyridine results in highly efficient and metabolically stable inhibitors relative to C2-alkylamino derivatives. A series of novel candidates was investigated for metabolic stability in human liver microsomes and in human whole blood. Additionally, metabolic S-oxidation was investigated, and possible metabolites were synthesized. [source] SyGMa: Combining Expert Knowledge and Empirical Scoring in the Prediction of MetabolitesCHEMMEDCHEM, Issue 5 2008Lars Ridder Dr. Abstract Predictions of potential metabolites based on chemical structure are becoming increasingly important in drug discovery to guide medicinal chemistry efforts that address metabolic issues and to support experimental metabolite screening and identification. Herein we present a novel rule-based method, SyGMa (Systematic Generation of potential Metabolites), to predict the potential metabolites of a given parent structure. A set of reaction rules covering a broad range of phase,1 and phase,2 metabolism has been derived from metabolic reactions reported in the Metabolite Database to occur in humans. An empirical probability score is assigned to each rule representing the fraction of correctly predicted metabolites in the training database. This score is used to refine the rules and to rank predicted metabolites. The current rule set of SyGMa covers approximately 70,% of biotransformation reactions observed in humans. Evaluation of the rule-based predictions demonstrated a significant enrichment of true metabolites in the top of the ranking list: while in total, 68,% of all observed metabolites in an independent test set were reproduced by SyGMa, a large part, 30,% of the observed metabolites, were identified among the top three predictions. From a subset of cytochrome P450 specific metabolites, 84,% were reproduced overall, with 66,% in the top three predicted phase,1 metabolites. A similarity analysis of the reactions present in the database was performed to obtain an overview of the metabolic reactions predicted by SyGMa and to support ongoing efforts to extend the rules. Specific examples demonstrate the use of SyGMa in experimental metabolite identification and the application of SyGMa to suggest chemical modifications that improve the metabolic stability of compounds. [source] The Trifluoroethylamine Function as Peptide Bond ReplacementCHEMMEDCHEM, Issue 12 2007Monica Sani Dr. 3D instead of 2D. That's the main difference between the tetrahedral stereogenic trifluoroethylamine function and the planar peptide bond. This property, together with other remarkable features such as high metabolic stability and low basicity, turns out to be of great importance to allow trifluoroethylamines to be excellent peptide bond replacements. [source] | |||||||||||||