Current opinion in drug discovery & development最新文献

Type 2 diabetes (T2D) and associated obesity have reached epidemic proportions, and there is an increasing need for orally effective agents that regulate glucose homeostasis with a concurrent reduction in body weight. GPR119, a class-A (rhodopsin-like) G protein-coupled receptor, expressed primarily in the human pancreas and gastrointestinal tract, has attracted considerable interest as a T2D drug target in the last three to five years. The activation of GPR119 increases the intracellular accumulation of cAMP, leading to enhanced glucose-dependent insulin secretion and increased levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide). In rodent models, orally available GPR119-specific agonists have been shown to attenuate blood glucose levels with a simultaneous body weight loss. This review summarizes the research leading to the identification of GPR119 as a potential drug target for T2D and related metabolic disorders. In addition, an overview of the recent progress made in the discovery of orally active GPR119 agonists is provided.

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) have attracted significant interest in the pharmaceutical industry as potential therapies for a variety of diseases of the CNS. Well-characterized small-molecule mGluR5 NAMs have demonstrated efficacy in several preclinical models of disease, and examples of the clinical efficacy of such NAMs have been reported in recent years. Advances, both in the discovery and development of new small molecules and in the clinical evaluation of known compounds, have been significant in the past 2 years. Recent progress in preclinical drug discovery efforts has used multiple strategies for the discovery of new chemical scaffolds, including the structural modification of known compounds, the rational design of new chemical scaffolds based on known compounds, and the development of screening approaches for new, structurally distinct scaffolds. Progress in the clinical setting with mGluR5 NAMs has also resulted in important recent advances, including the completion of proof-of-concept studies.

Personalized medicine is a custom-tailored approach to patient treatment based on individual genetic traits. In personalized medicine, a patient group is characterized by a clinical biomarker that has been correlated to a differential response to drug treatment. During the past decade, several developments in the understanding of the structure and function of the human genome have occurred that bring personalized medicine closer to becoming a reality. The promise of personalized medicine lies in a clinical biomarker-driven patient stratification, and focused smaller-sized clinical trials that result in a shorter development time and reduced overall development cost. Personalized medicine has the potential to offer a new business model for the pharmaceutical industry by providing a more efficient drug discovery process with reduced cost.

Anticoagulant use is recommended for the prevention and treatment of several thromboembolic disorders including venous thromboembolism. However, anticoagulants are often underprescribed because of the disadvantages associated with conventional agents, including the requirement for routine clinical monitoring and parenteral administration. Recent research has focused on the development of agents that target specific factors in the coagulation cascade, primarily Factor (F)Xa and thrombin. There are several new, targeted oral anticoagulants in development that could potentially provide more effective and more convenient anticoagulation than conventional agents. This review provides an update on clinical trials of the direct FXa and thrombin inhibitors.

Neuropathic pain is a chronic disease, which impacts millions of individuals worldwide. The condition is currently treated with several drugs that provide pain relief that is inconsistent and complicated by CNS or cardiovascular (CV) side effects. Voltage-gated sodium channels (VGSCs) and voltage-gated calcium channels (VGCCs) are of particular interest as targets for neuropathic pain because they control electrical signals in both the central and peripheral nervous system. Recent research has demonstrated that the expression of voltage-gated ion channels changes significantly under conditions of neuropathic pain in rodents and humans. Selective modulation of the channels involved in the pathology of the disease, while sparing the channels that are essential for normal nociception, offers promising opportunities for therapeutic intervention. This review summarizes recent developments of small molecules that target VGSCs and VGCCs.

Schizophrenia is a severe neuropsychiatric disorder for which there is no adequate current treatment. Recent theories about the molecular basis of schizophrenia focus on disturbances of glutamatergic neurotransmission, particularly at NMDA-type glutamate receptors (NMDARs). NMDARs are regulated in vivo by the amino acids glycine and D-serine. Glycine levels, in turn, are regulated by glycine transporter type 1 (GlyT1), which serves to maintain low subsaturating glycine levels in the vicinity of the NMDAR. Therefore, one proposed approach to the treatment of schizophrenia is via the inhibition of GlyT1-mediated transport. During the past decade, several well-tolerated, high-affinity glycine transport inhibitors (GTIs) have been developed that demonstrate the ability to potentiate NMDAR-mediated neurotransmission in animal models relevant to schizophrenia. In addition, clinical trials have been conducted with sarcosine (N-methylglycine), a naturally occurring GTI. Issues related to clinical proof-of-concept studies with high-affinity GTIs in schizophrenia are discussed in this review.

Human respiratory syncytial virus (hRSV) is a significant cause of respiratory illness in at-risk pediatric patients, immunocompromised adults and the elderly. No vaccine is currently available for the virus and treatment options are limited to the prophylactic treatment of at-risk infants with the mAb palivizumab (Synagis) and to therapeutic intervention with the nucleoside analog ribavirin (Rebetol). The clinical use of these agents is limited and a need exists for more effective treatment for the at-risk population. The merging of viral and cellular membranes is a crucial event in the hRSV life cycle that enables the virus to enter a host cell. The multistep fusion process is facilitated by the substantial refolding of a trimeric class I fusion protein (F protein), which is the main target of fusion inhibitors. Several small-molecule fusion inhibitors have been discovered, of which some have progressed significantly in the drug development process. BTA-9881 (Biota Holdings Ltd/MedImmune) and TMC-353121 (Johnson & Johnson) are the most advanced of this drug class. In addition, progress has been made in the development of next-generation antibodies such as motavizumab (Numax; MedImmune). This review will discuss the status and latest developments of compounds and antibodies that inhibit hRSV fusion.

Physiologically based pharmacokinetics (PBPK) models are increasingly being used in the lead optimization (LO) process. Although there are currently few literature reports of the application of PBPK, the scope of PBPK modeling is expanding and there is a steady increase in the number of publications in this field. Recent publications covering four important areas of the application of PBPK modeling in LO have been reviewed.

A number of current trends that are being adopted to reshape the field of high-performance computing exist, including multi-core systems, accelerators, and software frameworks for large-scale intrinsically parallel applications. These trends intersect with recent developments in computational chemistry to provide new capabilities for computer-aided drug discovery. Although this review focuses primarily on the application domains of molecular modeling and biomolecular simulation, these computing changes are relevant for other computationally intensive tasks, such as instrument data processing and chemoinformatics.

The rapidly increasing quantity of protein sequence data continues to widen the gap between available sequences and annotations. Comparative modeling suggests some aspects of the 3D structures of approximately half of all known proteins; homology- and network-based inferences annotate some aspect of function for a similar fraction of the proteome. For most known protein sequences, however, there is detailed knowledge about neither their function nor their structure. Comprehensive efforts towards the expert curation of sequence annotations have failed to meet the demand of the rapidly increasing number of available sequences. Only the automated prediction of protein function in the absence of homology can close the gap between available sequences and annotations in the foreseeable future. This review focuses on two novel methods for automated annotation, and briefly presents an outlook on how modern web software may revolutionize the field of protein sequence annotation. First, predictions of protein binding sites and functional hotspots, and the evolution of these into the most successful type of prediction of protein function from sequence will be discussed. Second, a new tool, comprehensive in silico mutagenesis, which contributes important novel predictions of function and at the same time prepares for the onset of the next sequencing revolution, will be described. While these two new sub-fields of protein prediction represent the breakthroughs that have been achieved methodologically, it will then be argued that a different development might further change the way biomedical researchers benefit from annotations: modern web software can connect the worldwide web in any browser with the 'Deep Web' (ie, proprietary data resources). The availability of this direct connection, and the resulting access to a wealth of data, may impact drug discovery and development more than any existing method that contributes to protein annotation.