Current opinion in drug discovery & development最新文献

Molecularly targeted therapies have been increasingly incorporated into standard treatment regimens for the majority of hematological malignancies. To increase the efficacy of the next generation of drugs, research efforts have been aimed at identifying molecular defects specific to leukemic cells. A significant therapeutic opportunity is represented by the possibility of selectively eradicating the leukemic stem cell pool. This review focuses on new insights regarding oncogenetic mechanisms in hematological malignancies and related possible druggable targets, including the pathways leading to leukemic stem cell maintenance and the specific approaches used to eliminate them.

Since 2008, significant advances have been made in understanding the role of diacylglycerol acyl transferase-1 (DGAT1) in disease states such as diabetes and obesity. Gene deletion and overexpression studies have provided important new insights into the function of DGAT1, as have the first reports from preclinical models of small-molecule inhibitor effects, which are discussed in this review in relation to the phenotypes of DGAT knockout and overexpression models. The progress of medicinal chemistry efforts has resulted in a new generation of DGAT1 inhibitors that have progressed into clinical development, with the leading compound LCQ-908 (Novartis AG) now in phase II clinical trials. This exciting progress has led researchers to anticipate that an understanding of the human pharmacology of DGAT1 inhibitors, as well as their potential as therapeutic agents for the treatment of diabetes and obesity, will be achieved in the next few years.

Thermal shift assays are one of the label-free technologies gaining popularity in drug discovery and academic research. This review summarizes the various detection formats used in these assays, and provides an in-depth presentation of fluorescence-based thermal shift assays. The dual applications of stability profiling and affinity ranking are highlighted, and basic experimental protocol and data analysis algorithms are recommended. The advantages and limitations of the technology are also discussed to provide guidance for meaningful data interpretation. In addition, an emerging paradigm is described that incorporates thermal shift assays with other label-free biosensors and conventional IC(50) assays to derive a mechanism of action-informed SAR in lead identification and optimization during drug discovery.

Chemokines and chemokine receptors form a complex and diverse system known to be relevant for leukocyte activation and trafficking. There has been significant interest in the development of anti-inflammatory drugs that antagonize the function of chemokines or their receptors. However, the translation of results from animal models to human disease has not been simple, and drug development in the field has failed in many instances, leading to the question of whether targeting several chemokines may be more useful than targeting a single chemokine or receptor. This question has no simple answer. The complexity of the chemokine system may result in functional redundancy, which is not absolute. However, this complexity is likely important for the physiology of the immune system. The success of future development of therapies targeting chemokines and their receptors requires a complete understanding of the diversity and complexity of the system in human chronic inflammatory diseases and infection.

Antagonism of the adenosine A2A receptor has emerged as a promising non-dopaminergic approach for the potential treatment of Parkinson's disease (PD). Several pharmaceutical and academic institutions have ongoing research programs in this area, and orally efficacious A2A receptor antagonists have been advanced into clinical development. Traditionally, antagonists of the A2A receptor are classified as xanthine and non-xanthine derivatives. This review provides a detailed summary of the recent SAR development that has led to the discovery of promising non-xanthine-based A2A receptor antagonists. The current clinical status and the potential utility of A2A receptor antagonists in indications other than PD are also discussed.

The liver X receptors LXRalpha and LXRbeta regulate the expression of genes promoting cellular cholesterol efflux and the formation of HDL particles, and are atheroprotective. However, LXRalpha and LXRbeta also regulate the expression of genes involved in lipogenesis and hypertriglyceridemia. The identification of efficacious LXR modulators that are devoid of undesirable side effects remains a significant challenge for drug development. The X-ray structures of many LXR protein/small-molecule complexes have revealed that the ligand-binding pockets of LXRalpha and LXRbeta, despite being highly conserved, are large and flexible; these properties have allowed the design of a wide range of ligands with varied selectivity profiles. This review discusses the latest medicinal chemistry strategies used to derive novel LXR modulators with the potential for enhanced therapeutic utility and safety, and summarizes the current status of compounds that have progressed into clinical development.

Interest in sphingosine-1-phosphate (S1P)(1) receptor agonists has increased steadily since the discovery that the mechanism of action of fingolimod (FTY-720)-induced lymphopenia is linked to the S1P GPCR family. Fingolimod is an agonist at four out of the five S1P family receptors. Adoptive cell transfer experiments and selective S1P(1) receptor agonists provided evidence that the S1P(1) receptor is the main target responsible for trapping lymphocytes in secondary lymphoid tissue. This readily accessible, translatable biomarker has been correlated with efficacy in rodent models of immune disease. Novartis AG filed for regulatory approval for fingolimod in the US and EU for the treatment of multiple sclerosis in December 2009. In addition, more selective compounds targeting S1P receptors from several companies have entered clinical trials. These compounds can be categorized into two classes of S1P(1) receptor agonists: amino alcohol prodrugs and second-generation direct agonists. This review focuses on the development of these compounds and the role of S1P receptor family selectivity.

mTOR is a serine-threonine kinase that plays a key role in the regulation of cellular growth. The mTOR pathway consists of two distinct complexes: mTOR/Raptor (mTORC1) and mTOR/Rictor (mTORC2). In response to changes in the levels of insulin, nutrients and energy supply, signaling through these complexes affects a variety of processes, including protein translation and cell proliferation. The efficacy of derivatives of the natural product rapamycin (sirolimus), which functions as an allosteric inhibitor of mTORC1, has validated mTOR inhibition as an anticancer treatment. More recently, extensive efforts have been focused on the discovery of ATP-competitive inhibitors of mTOR that would inhibit both mTORC1 and mTORC2 and may provide additional clinical benefit. This review provides a summary of recent research efforts in this field, focusing on mTOR inhibitors that are selective for mTOR over the related lipid kinase PI3K.

Antiplatelet therapy is a crucial component of disease management for patients with acute coronary syndromes or chronic stable coronary disease, as well as individuals undergoing percutaneous coronary intervention with stent implantation. Antiplatelet therapy includes the administration of aspirin and clopidogrel, either alone or in combination, which act through the inhibition of thromboxane A2 generation and blockade of the Gi-coupled P2Y12 purinergic receptor, respectively. Because of the selective expression and specific functions of P2Y12 , this receptor has become an important antiplatelet drug target. P2Y12 antagonists can be broadly classified as either irreversible or reversible. Clopidogrel, an irreversible P2Y12 antagonist, has a delayed onset of action and high inter-individual variability. Limitations of clopidogrel have necessitated the discovery of novel P2Y12 antagonists with superior pharmacological profiles. This review summarizes recent studies on novel P2Y12 antagonists and the clinical implications and limitations of these agents.

The cloning of the three tachykinin receptors in the late 1980s formed the basis of intense preclinical research efforts into the systems relating to the tachykinin receptors, as well as compound screening campaigns. Remarkably, orally active non-peptide antagonists were successfully identified for all three of the tachykinin receptors, providing tools for further evaluation of the pharmacology of these receptor systems. The NK3 receptor (mammalian tachykinin receptor 3), which exhibited a discrete expression pattern and the modulatory regulation of various transmitter systems in the CNS, has attracted significant interest. Preclinical studies demonstrated that the NK3 receptor might be a promising target for CNS disorders, and clinical trials with non-peptide NK3 receptor antagonists have been performed for indications such as schizophrenia, major depressive disorder, panic attacks and Parkinson's disease. In particular, the positive results of the schizophrenia meta-trial with osanetant increased the focus on the NK3 receptor system and its clinical potential. Consequently, a significant number of patents covering non-peptide antagonists for the NK3 receptor have been published during the past decade. This review describes the most recent NK3 receptor antagonists (published from 2004 to 2009), which are classified into seven unique templates.