Systematic Approach to Organizing Structural Alerts for Reactive Metabolite Formation from Potential Drugs.

Reactive metabolites are widely accepted as playing a pivotal role in causing idiosyncratic adverse drug reactions (IDR). However, much is unknown about the biological mechanisms of IDR, although the initiating event in most cases is an attachment of a reactive intermediate to macromolecules leading to immune-mediated responses. Reactive metabolites are also involved in many mutagenesis/carcinogenesis events by reacting with DNA. Drug designers thus have reasons to make large efforts to avoid making test compounds having a liability to generate reactive metabolites. In this Perspective we argue for using structural alerts (SA) as the most straightforward way to link forecasting about chemical hazards of planned test compounds to the accumulated knowledge base. Although many SAs have been widely recognized and reviewed previously, there are also a lot of observations that have no readily discernible chemical interpretation. For drug designers to benefit from all published data, the knowledge has to be organized in a way that is readily searchable starting with a query structure. We propose that an increased number of structural alerts with more details should be applied to obtain improved decision support. The association of selected SAs with reference drugs, whose proposed or hypothesized activation mechanisms build the knowledge base, should be readily available in a format comprising of small summaries with included hyperlinks for quick access to the original literature, as outlined in the TOC illustration. Since some structural alerts are present in drugs that do not cause idiosyncratic adverse reactions or drug-drug interactions, it is important to elaborate on the reasons for this discrepancy as much as possible.

Discovery and characterization of AZD9272 and AZD6538-Two novel mGluR5 negative allosteric modulators selected for clinical development.

AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.

Phenethyl nicotinamides, a novel class of Na(V)1.7 channel blockers: structure and activity relationship.

The Na(V)1.7 ion channel is an attractive target for development of potential analgesic drugs based on strong genetic links between mutations in the gene coding for the channel protein and inheritable pain conditions. The (S)-N-chroman-3-ylcarboxamide series, exemplified by 1, was used as a starting point for development of new channel blockers, resulting in the phenethyl nicotinamide series. The structure and activity relationship for this series was established and the metabolic issues of early analogues were addressed by appropriate substitutions. Compound 33 displayed acceptable overall in vitro properties and in vivo rat PK profile.

N-1-Alkyl-2-oxo-2-aryl amides as novel antagonists of the TRPA1 receptor.

A series of potent antagonists of the ion channel transient receptor potential A1 (TRPA1) was developed by modifying lead structure 16 that was discovered by high-throughput screening. Based on lead compound 16, a SAR was established, showing a narrow region at the nitro-aromatic R(1) moiety and at the warhead, while the R(2) side had a much wider scope including ureas and carbamates. Compound 16 inhibits Ca(2+)-activated TRPA1 currents reversibly in whole cell patch clamp experiments, indicating that under in vivo conditions, it does not react covalently, despite its potentially electrophilic ketone.

Efficient chemoenzymatic dynamic kinetic resolution of 1-heteroaryl ethanols.

The scope and limitation of the combined ruthenium-lipase induced dynamic kinetic resolution (DKR) through O-acetylation of racemic heteroaromatic secondary alcohols, i.e., 1-heteroaryl substituted ethanols, was investigated. After initial screening of reaction conditions, Candida antarctica lipase B (Novozyme 435, N435) together with 4-chloro-phenylacetate as acetyl-donor for kinetic resolution (KR), in conjunction with the ruthenium-based Shvo catalyst for substrate racemization in toluene at 80 degrees C, enabled DKR with high yields and stereoselectivity of various 1-heteroaryl ethanols, such as oxadiazoles, isoxazoles, 1H-pyrazole, or 1H-imidazole. In addition, DFT calculations based on a simplified catalyst complex model for the catalytic (de)hydrogenation step are in agreement with the previously reported outer sphere mechanism. These results support the further understanding of the mechanistic aspects behind the difference in reactivity of 1-heteroaryl substituted ethanols in comparison to reference substrates, as often referred to in the literature.

Structure-activity relationship of thiopyrimidines as mGluR5 antagonists.

Structure-activity relationship investigations of the thiopyrimidine (1), an HTS hit with micromolar activity as a metabotropic glutamate receptor 5 (mGluR5) antagonist, led to compounds with sub-micromolar activity.

Recent advances in non-competitive mGlu5 receptor antagonists and their potential therapeutic applications.

Extensive research into the functions of glutamate and glutamate receptors in the central nervous system (CNS) has shown an essential role of metabotropic glutamate (mGlu) receptors in normal brain functions, but also in neurological and psychiatric disorders. The precise functions of these receptors remain undefined, and progress toward understanding their functions has been hampered by the lack of selective ligands with appropriate pharmacokinetic properties. The Group I mGlu receptor, mGlu5, is well positioned to regulate and fine-tune neuronal excitability and synaptic transmission through its modulation of various signal transduction pathways and interactions with other transmitter systems. Therefore, the mGlu5 receptor may be an important therapeutic target for the treatment of disorders of the central nervous system. The discovery of MPEP 3, a non-competitive mGlu5 receptor antagonist, provided a potent, selective, systemically active tool compound for proof of concept studies in animal models of various disease states. These studies have led to greater understanding of possible therapeutic applications of mGlu5 receptor antagonists in recent years, suggesting their use in a number of disease states, including chronic pain, various psychiatric and neurological disorders, substance abuse and withdrawal, obesity and gastroesophageal reflux disease (GERD). Together, these findings have intensified efforts to find other non-competitive mGlu5 receptor antagonists and have led to the discovery of several second-generation compounds, a few of which are in preclinical evaluations. There have been several recent reviews on mGlu receptor. This article highlights recent efforts on the design, synthesis and development of novel, non-competitive mGlu5 receptor antagonists and studies to understand their in vitro mechanisms of action and in vivo pharmacological profiles. Emphasis is also given to recent advances in the potential therapeutic applications of non-competitive mGlu5 receptor antagonists.