Carbamates and ICH M7 classification: Making use of expert knowledge.

Carbamates are widely used in the chemical industry so understanding their toxicity is important to safety assessment. Carbamates have been associated with certain toxicities resulting in publication of structural alerts, including alerts for mutagenicity. Structural alerts for bacterial mutagenicity can be used in combination with statistical systems to enable ICH M7 classification, which allows assessment of the genotoxic risk posed by pharmaceutical impurities. This study tested a hypothetical bacterial mutagenicity alert for carbamates and examined the impact it would have on ICH M7 classifications using (Q)SAR predictions from the expert rule-based system Derek Nexus and the statistical-based system Sarah Nexus. Public datasets have a low prevalence of mutagenic carbamates, which highlighted that systems containing an alert for carbamates perform poorly for achieving correct ICH M7 classifications. Carbamates are commonly used as protecting groups and proprietary datasets containing such compounds were also found to have a low prevalence of mutagenic compounds. Expert review of the mutagenic compounds established that mutagenicity was often only observed under certain (non-standard) conditions and more generally that the Ames test may be a poor predictor for the risk of carcinogenicity posed by chemicals in this class. Overall a structural alert for the in vitro bacterial mutagenesis of carbamates does not benefit workflows for assigning ICH M7 classification to impurities.

Proteome-wide reactivity profiling identifies diverse carbamate chemotypes tuned for serine hydrolase inhibition.

Serine hydrolases are one of the largest and most diverse enzyme classes in Nature. Inhibitors of serine hydrolases are used to treat many diseases, including obesity, diabetes, cognitive dementia, and bacterial and viral infections. Nonetheless, the majority of the 200+ serine hydrolases in mammals still lack selective inhibitors for their functional characterization. We and others have shown that activated carbamates, through covalent reaction with the conserved serine nucleophile of serine hydrolases, can serve as useful inhibitors for members of this enzyme family. The extent to which carbamates, however, cross-react with other protein classes remains mostly unexplored. Here, we address this problem by investigating the proteome-wide reactivity of a diverse set of activated carbamates in vitro and in vivo, using a combination of competitive and click chemistry (CC)-activity-based protein profiling (ABPP). We identify multiple classes of carbamates, including O-aryl, O-hexafluoroisopropyl (HFIP), and O-N-hydroxysuccinimidyl (NHS) carbamates that react selectively with serine hydrolases across entire mouse tissue proteomes in vivo. We exploit the proteome-wide specificity of HFIP carbamates to create in situ imaging probes for the endocannabinoid hydrolases monoacylglycerol lipase (MAGL) and α-ß hydrolase-6 (ABHD6). These findings, taken together, designate the carbamate as a privileged reactive group for serine hydrolases that can accommodate diverse structural modifications to produce inhibitors that display exceptional potency and selectivity across the mammalian proteome.

O-hydroxyacetamide carbamates as a highly potent and selective class of endocannabinoid hydrolase inhibitors.

The two major endocannabinoid transmitters, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are degraded by distinct enzymes in the nervous system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. FAAH and MAGL inhibitors cause elevations in brain AEA and 2-AG levels, respectively, and reduce pain, anxiety, and depression in rodents without causing the full spectrum of psychotropic behavioral effects observed with direct cannabinoid receptor-1 (CB1) agonists. These findings have inspired the development of several classes of endocannabinoid hydrolase inhibitors, most of which have been optimized to show specificity for either FAAH or MAGL or, in certain cases, equipotent activity for both enzymes. Here, we investigate an unusual class of O-hydroxyacetamide carbamate inhibitors and find that individual compounds from this class can serve as selective FAAH or dual FAAH/MAGL inhibitors in vivo across a dose range (0.125-12.5 mg kg(-1)) suitable for behavioral studies. Competitive and click chemistry activity-based protein profiling confirmed that the O-hydroxyacetamide carbamate SA-57 is remarkably selective for FAAH and MAGL in vivo, targeting only one other enzyme in brain, the additional 2-AG hydrolase ABHD6. These data designate O-hydroxyacetamide carbamates as a versatile chemotype for creating endocannabinoid hydrolase inhibitors that display excellent in vivo activity and tunable selectivity for FAAH-anandamide versus MAGL (and ABHD6)-2-AG pathways.

Schedules of controlled substances: placement of ezogabine into Schedule V. Final rule.

With the issuance of this final rule, the Administrator of the Drug Enforcement Administration (DEA) places the substance ezogabine, including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible, into Schedule V of the Controlled Substances Act (CSA). This action is pursuant to the CSA which requires that such actions be made on the record after opportunity for a hearing through formal rulemaking.

Strategies for the development of novel Taxol-like agents.

Taxol, the first microtubule stabilizer identified, is one of the most important new anticancer drugs to be brought to the clinic in the past 20 yr. The clinical success of TaxolTM led to the development of a second-generation taxane, docetaxel (Taxotere), and multiple third-generation taxane derivatives are under development. Non-taxane microtubule-stabilizers of diverse chemical structures, including the epothilones and discodermolide, show promising preclinical activities and several epothilones are progressing through clinical trials. One important advantage of the new stabilizers is their ability to circumvent drug resistance mechanisms. The clinical development of these new classes of agents suggests that microtubule stabilizers will continue to be important drugs for the treatment of cancer. This chapter provides a brief history of Taxol and the discovery and development status of other classes of microtubule stabilizers. Although all microtubule-stabilizers share similar mechanisms of action, interesting subtle differences among the stabilizers are being detected. This chapter also provides some strategies for identifying the differences among microtubule stabilizers that may help prioritize them for development and clinical use.

The use of artificial neural networks for the selection of the most appropriate thermal parameters and for the classification of a set of phenylcarbamic acid derivates.

The objective of this work was to apply artificial neural networks (ANNs) to the classification group of 43 derivatives of phenylcarbamic acid. To find the appropriate clusters Kohonen topological maps were employed. As input data, thermal parameters obtained during DSC and TG analysis were used. Input feature selection (IFS) algorithms were used in order to give an estimate of the relative importance of various input variables. Additionally, sensitivity analysis was carried out to eliminate less important thermal variables. As a result, one classification model was obtained, which can assign our compounds to an appropriate class. Because the classes contain groups of molecules structurally related, it is possible to predict the structure of the compounds (for example the position of the substitution alkoxy group in the phenyl ring) on the basis of obtained parameters.

Quantitative structure-activity relationships for the toxicity of organophosphorus and carbamate pesticides to the Rainbow trout Onchorhyncus mykiss.

This study has investigated the development of quantitative structure-activity relationships (QSARs) for the toxicity to rainbow trout Onchorhyncus mykiss Walbaum of 75 organophosphorus and carbamate pesticides. The toxicity data were obtained from an openly available toxicological database and were selected to be representative of a single endpoint. A large number of physicochemical and structural descriptors were calculated for the pesticides. QSAR models were developed using multiple linear regression and partial least-squares analyses. Following the removal of a small number of outliers, predictive QSARs were developed on small numbers of mechanistically relevant descriptors. Applying mechanistic knowledge to the development of QSAR further improved predictivity.

Repaglinide--a new compound for the treatment of patients with type 2 diabetes.

Repaglinide is a new oral blood glucose lowering agent, a member of the carbamoylmethyl benzoic acid (CMBA) family. Its mechanism of action is partly similar to that of the sulphonylurea: the release of insulin from the pancreatic beta cells is stimulated by closure of ATP-dependent potassium channels. However, repaglinide regulates these channels via a different binding site on the beta cell than glibenclamide, and the drug does not cause insulin release in the absence of glucose, or during voltage-clamping. After oral administration the drug is rapidly absorbed and eliminated. It is therefore used in a meal-related dosing regimen; repaglinide is taken with each main meal. This meal-related use may give a more physiological mimick of daytime insulin requirement than once-daily or twice-daily use of sulphonylurea. Patients using repaglinide are less likely to develop hypoglycaemic symptoms when they miss or postpone a meal in comparison with patients on glibenclamide treatment. In long-term comparative phase 3 clinical studies it was found that repaglinide is equally effective in maintaining glycaemic control as existing sulphonylurea, but it gives significantly better control of postprandial blood glucose levels. Repaglinide can be used as monotherapy both in obese and non-obese type 2 diabetic patients, and is also very effective in combination with drugs like metformin or thiazolidines. Because of its excretion through liver and bile it is also an attractive drug for diabetic patients with diminished kidney function, especially the elderly diabetic. Although the overall incidence of hypoglycaemia was similar during use of repaglinide and of sulphonylurea, fewer serious hypoglycaemic episodes were observed in repaglinide-treated patients.