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- ArticleMichne WF.Curr Top Med Chem. 2005;5(4):369.
- ArticleZamponi GW.Curr Top Med Chem. 2005;5(6):527.
- ArticleBenamouzig R, Uzzan B, Little J, Chaussade S.Curr Top Med Chem. 2005;5(5):493-503.Chemoprevention of colorectal cancer involves the long-term use of pharmacologic agents that can prevent neoplasms from developing in the large bowel. This new approach requires major funding and human investments. Among the most widely studied agents for the chemoprevention of colorectal cancer, aspirin, the NSAIDs and COX-2 inhibitors seem to be the most promising. A large number of observational epidemiological studies show that regular use of aspirin and other NSAIDs is associated with a reduction in the risk of developing both colorectal adenomas and cancer. In addition, the prodrug sulindac reduces the growth of existing polyps in familial adenomatous polyposis (FAP). However, the dose, duration of effect and length of protection seen after cessation remain to be fully established. Furthermore, in view of previous discrepancies between the results of observational studies and randomized control trials (RCTs), it is crucially important to investigate the effects of aspirin by RCTs. RCTs investigating the effect of chemopreventive agents on adenoma recurrence as an intermediate endpoint for colorectal cancer is a more feasible approach than RCTs to investigate the effect on the incidence if colorectal cancer per se. Four RCTs of the effect of aspirin on adenoma recurrence are available. Other trials are currently underway.
- ArticleDe Sarro G, Gitto R, Russo E, Ibbadu GF, Barreca ML, De Luca L, Chimirri A.Curr Top Med Chem. 2005;5(1):31-42.Over the last years alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs) have been intensively studied owing to their crucial role in physiological and pathological processes. Efforts targeting AMPAR have been focused on identification of ligands as potential therapeutic agents useful in the prevention and treatment of a variety of neurological and non-neurological diseases. In particular, extensive work was addressed to the discovery of selective antagonists some of which proved to be potent anticonvulsant agents.
- ArticleMcGaraughty S, Cowart M, Jarvis MF, Berman RF.Curr Top Med Chem. 2005;5(1):43-58.Adenosine (ADO) acts as an inhibitory neuromodulator throughout the central and peripheral nervous system and can regulate seizure and nociceptive activity. However, the positive actions of systemically administered ADO are usually accompanied by undesirable side effects such as hypomobility and cardio-suppression. Adenosine kinase (AK) is the primary metabolic enzyme regulating intra- and extracellular concentrations of ADO. We review the recent development of structurally novel nucleoside and nonnucleoside AK inhibitors that demonstrate high specificity for the AK enzyme. Several of these compounds have shown significant beneficial effects in animal models of epilepsy and pain with an improved preclinical therapeutic window over direct acting ADO receptor agonists.
- ArticleGooden DM, Chakrapani H, Toone EJ.Curr Top Med Chem. 2005;5(7):687-705.Because of the chemical and physical properties of nitric oxide, its effective use and delivery for therapeutic application represents a significant challenge. Accordingly, current understanding of nitric oxide biology largely stems from the use of nitric oxide prodrugs and adducts whose biological activities are based on their ability to release nitric oxide or a redox-related species. Among the structurally diverse ensemble of nitric oxide donor compounds reported to date are the C-nitroso compounds. These compounds have only recently been investigated with respect to their potential as nitric oxide donors, although they have been known and studied for over 120 years. Here, we consider the synthesis and physico-chemical properties of the C-nitroso compounds and the available data regarding their biological activities. Synthetic methods reviewed include direct substitution of H by NO, oxidative approaches, and the addition of various oxides of nitrogen across multiple bonds. The electronic spectra of C-nitroso compounds and the mechanism and thermodynamics of monomer-dimer equilibration are described. The physico-chemical and biological properties of two related classes of compounds, the diazetine dioxides and the furoxans, are also described.
- ArticleShoulders CC, Shelness GS.Curr Top Med Chem. 2005;5(3):283-300.The microsomal triglyceride transfer protein (MTP), along with its partner, protein disulphide isomerase, performs a wide range of lipid transport functions necessary for maintenance of whole-body lipid homeostasis. In this review, we summarize the recent deluge of comparative and functional genomic data that have forced a radical re-appraisal of the evolutionary processes that established the major lipid transport pathway in man, and the different structural and lipid transfer roles MTP plays within it. This is followed by an overview of MTP structure-function relationships, highlighting two newly identified functional roles: first, the production of small, apolipoprotein (apo)B-containing lipoprotein particles in cardiac myocytes and, second, the lipidation of a major histocompatibility complex class-I related molecule (CD1d) that presents glycolipid antigens to distinct subsets of natural killer T cells. We also discuss the interactions of MTP with proteins such as apoB and CD1d, and the complex mechanisms regulating MTP transcription in different cell types and nutritional states. The past five years has witnessed remarkable progress in teasing out the different functionalities of MTP, and the properties of the different molecules that inhibit MTP activity, data that are likely to underpin the design of the next generation of MTP/apoB inhibitors for preventing cardiovascular disease attributable to the increased production of atherogenic lipoproteins.
- ArticleThatcher GR.Curr Top Med Chem. 2005;5(7):597-601.Investigational NO-related therapeutic agents span the range from prodrugs that elevate NO levels, to scavengers of NO, and inhibitors of endogenous NO synthesis. Related agents that influence nitrogen oxides, in addition to NO itself, are also to be considered. Organic nitrates have been used for over 130 years in cardiovascular therapy and hybrid nitrates continue to lead the way in clinical development for an increasing range of disease states. Selectivity for inhibition of NO synthase (NOS) isoforms is a continuing goal. Conversely, N-hydroxyarginine derivatives are substrates for NOS and represent a new NO donor class. Diazeniumdiolate (NONOate) NO donors have been essential for understanding of NO biology and are being developed as NO donor and HNO donor prodrugs including as photolabile sources. N-Hydroxyurea has been used as a cancer drug for decades and is approved for sickle cell disease treatment, but also provides a lead compound for design of NO and HNO donors. Nitroaliphatics and nitrosoaliphatics also represent chemical classes that include NO donors and exhibit biological activity that mimics that of NO. Nitroprusside has been in use since the 1920's and metal ion complexes continue to be explored, including as caged NO donors. Clear and exciting opportunities exist for new therapies based upon NO-related drugs. Despite the extensive clinical use of NO donor drugs and the role of NOS activation in the action of several prescription medications, challenges remain to the development of new NO-related therapeutics, but these are surmountable and are outweighed by the opportunities.
- ArticleJacoby E, Schuffenhauer A, Popov M, Azzaoui K, Havill B, Schopfer U, Engeloch C, Stanek J, Acklin P, Rigollier P, Stoll F, Koch G, Meier P, Orain D, Giger R, Hinrichs J, Malagu K, Zimmermann J, Roth HJ.Curr Top Med Chem. 2005;5(4):397-411.The NIBR (Novartis Institutes for BioMedical Research) compound collection enrichment and enhancement project integrates corporate internal combinatorial compound synthesis and external compound acquisition activities in order to build up a comprehensive screening collection for a modern drug discovery organization. The main purpose of the screening collection is to supply the Novartis drug discovery pipeline with hit-to-lead compounds for today's and the future's portfolio of drug discovery programs, and to provide tool compounds for the chemogenomics investigation of novel biological pathways and circuits. As such, it integrates designed focused and diversity-based compound sets from the synthetic and natural paradigms able to cope with druggable and currently deemed undruggable targets and molecular interaction modes. Herein, we will summarize together with new trends published in the literature, scientific challenges faced and key approaches taken at NIBR to match the chemical and biological spaces.
- ArticleCzapiński P, Blaszczyk B, Czuczwar SJ.Curr Top Med Chem. 2005;5(1):3-14.Gamma-aminobutyric acid (GABA), one of the main inhibitory neurotransmitters in the brain, interacts with three types of receptors for GABA--GABA(A), GABA(B) and GABA(C). GABA(A) receptors, associated with binding sites for benzodiazepines and barbiturates in the form of a receptor complex, control opening of the chloride channel. When GABA binds to the receptor complex, the channel is opened and chloride anions enter the neuron, which is finally hyperpolarized. GABA(B) receptors are metabotropic, linked to a cascade of second messengers whilst the physiological meaning of ionotropic GABA(C) receptors, mainly located in the retina, is generally unknown. Novel antiepileptic drugs acting selectively through the GABA-ergic system are tiagabine and vigabatrin. The former inhibits neuronal and glial uptake of GABA whilst the latter increases the synaptic concentration of GABA by inhibition of GABA-aminotransferase. Gabapentin, designed as a precursor of GABA easily entering the brain, was shown to increase brain synaptic GABA. This antiepileptic drug also decreases influx of calcium ions into neurons via a specific subunit of voltage-dependent calcium channels. Conventional antiepileptics generally inhibit sodium currents (carbamazepine, phenobarbital, phenytoin, valproate) or enhance GABA-ergic inhibition (benzodiazepines, phenobarbital, valproate). Ethosuximide, mainly controlling absences, reduces calcium currents via T-type calcium channels. Novel antiepileptic drugs, mainly associated with an inhibition of voltage-dependent sodium channels are lamotrigine and oxcarbazepine. Since glutamate-mediated excitation is involved in the generation of seizure activity, some antiepileptics are targeting glutamatergic receptors--for instance, felbamate, phenobarbital, and topiramate. Besides, they also inhibit sodium currents. Zonisamide, apparently sharing this common mechanism, also reduces the concentration of free radicals. Novel antiepileptic drugs are better tolerated by epileptic patients and practically are devoid of important pharmacokinetic drug interactions.
- ArticleMalawska B.Curr Top Med Chem. 2005;5(1):69-85.The search for antiepileptic compounds with more selective activity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. This review describes new anticonvulsant agents representing various structures for which the precise mechanism of action is still not known. Many of the compounds presented in this review have been tested according to the procedure established by the Antiepileptic Drug Development Program of the Epilepsy Branch of the National Institute of Neurological Disorders and Stroke, National Institute of Health, USA. The newer agents include sulfonamides, amino acids, amides (analogs of gamma-vinyl GABA, N-benzylamides, 2,6-dimethylanilides, carboxyamides, hydroxyamides, alkanoamides); heterocyclic agents ((arylalkyl)imidazoles, pyrrolidin-2,5-diones, lactams, semi- thiosemicarbazones, thiadiazoles, quinazolin-4(3H)-ones, 2,5-disubstituted 1,2,4-thadiazoles, xanthones, derivatives of isatin) and enaminones. These new structural classes of compounds can prove useful for the design of future targets and development of new drugs.
- ArticleNatarajan SR, Doherty JB.Curr Top Med Chem. 2005;5(10):987-1003.The initial disclosure of tri-substituted imidazole-based drug molecules such as 1 for inhibition of p38 MAP kinase by SmithKline Beecham (SB) sparked an effort in this area at Merck and other pharmaceutical research establishments. Although analogs in this class have shown good inhibitory properties against p38 MAP kinase, their selectivity profile were modest and left much room for improvement. Attempts to discover newer compounds with improved selectivity over the prototypical SB compound 203580 (1), led to the discovery of a new sub-class of p38 inhibitors typified by compound 18 at Merck. Although this benchmark compound was potent, highly selective and orally efficacious it was burdened with compound related adverse effects in dogs that has delayed further development. In 1999, a new class of p38 inhibitors represented by clinical candidate VX-745 (26), was disclosed by Vertex Pharmaceuticals. This compound displayed unprecedented selectivity due to its unique mode of binding to the active site in p38 MAP kinase. Inspired by the exquisite selectivity profile of VX-745 [26] a scaffold re-design was initiated at Merck which resulted in the discovery of the quinazolinone, pyrimido-pyrimidone, pyrido-pyrimidone, quinolinone and naphthyridinone based p38 inhibitors.
- ArticleBajorath J.Curr Top Med Chem. 2005;5(8):797-803.Partitioning algorithms are described that operate in chemical reference spaces formed by combinations of binary-transformed molecular descriptors and aim at the identification of potent hits in ligand-based virtual screening. One of these approaches depends on mapping of consensus positions of compound activity sets in descriptor spaces followed by step-wise extension of the dimensionality of these spaces and re-mapping of activity-dependent consensus positions. Dimension extension is carried out to increase the discriminatory power of descriptor combinations and distinguish database compounds from potential hits. This method was originally named Dynamic Mapping of Consensus positions (DMC) and subsequently extended in order to take different potency levels of known active molecules into account and increase the probability of recognizing potent database hits. The extension was accomplished by adding potency scaling to DMC calculations, and the resulting approach was termed POT-DMC. Results of comparisons of DMC and POT-DMC calculations on different classes of active compounds with substantially varying potency levels support the validity of the POT-DMC approach.
- ArticleMortlock A, Keen NJ, Jung FH, Heron NM, Foote KM, Wilkinson R, Green S.Curr Top Med Chem. 2005;5(2):199-213.Errors in the mitotic process are thought to be one of the principal sources of the genetic instability that hallmarks cancer. Unsurprisingly, many of the proteins that regulate mitosis are aberrantly expressed in tumour cells when compared to their normal counterparts. These may represent a good source of targets for the development of novel anti-cancer agents. The Aurora kinases represent one such family of mitotic regulators. In recent years there has been intense interest in both understanding the role of the Aurora kinases in cell cycle regulation and also in developing small molecule inhibitors as potential novel anti-cancer drugs. With several companies now starting to take Aurora kinase inhibitors into clinical development, the time is right to review the medicinal chemistry contribution to developing the field, in particular to review the increasingly broad range of small molecule inhibitors with activity against this kinase family.
- ArticleSlassi A, Isaac M, Edwards L, Minidis A, Wensbo D, Mattsson J, Nilsson K, Raboisson P, McLeod D, Stormann TM, Hammerland LG, Johnson E.Curr Top Med Chem. 2005;5(9):897-911.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.
- ArticleIsaac M.Curr Top Med Chem. 2005;5(1):59-67.A variety of clinical observations suggest that certain forms of epilepsy are due to long-term, progressive changes in neural networks that eventually provoke spontaneous and recurring seizures. Recently, there has been growing evidence that serotonergic neurotransmission modulates experimentally induced seizures and is involved in the enhanced seizure susceptibility observed in some genetically epilepsy-prone animals. Generally, agents that elevate extracellular serotonin (5-Hydroxytryptamine, 5-HT) levels, such as 5-hydroxytryptophan, and 5-HT reuptake blockers inhibit both limbic and generalized seizures. Conversely, depletion of brain 5-HT lowers the threshold to audiogenically, chemically and electrically-evoked convulsions. More specifically, the recent finding that the 5-HT2B/2C receptor agonist, 1-(m-chlorophenyl)-piperazine (mCPP) is anticonvulsant has kindled an interest into the investigation of the serotonergic 5-HT2C receptor subtype as a potential target for the treatment of epilepsy. Further pharmacological evaluation of selective activation or inactivation of the 5-HT2C receptor subtype with selective agonist/positive modulators and antagonists will provide important information about the therapeutic contribution of this receptor to the epileptic circuitry in the brain. Future development of serotonergic antiepileptic drugs will be a significant addition to the therapeutic armamentarium against epilepsy.
- ArticleErrington AC, Stöhr T, Lees G.Curr Top Med Chem. 2005;5(1):15-30.Epilepsy is one of the most prevalent neurological syndromes in the world today. Epilepsy describes a group of brain disorders whose symptoms and causes are diverse and complicated, but all share a common behavioural manifestation: the seizure. Seizures result from the abnormal discharge of groups of neurons within the brain, usually within a focal point, that can result in the recruitment of large brain regions into epileptiform activity. Although the range of explanations for the development of seizures can be as varied as genetic composition to acute head trauma, the net result is often similar. The excitability of neurons is governed by the input they receive from their neighbours and the intrinsic excitability of the neuron. In this review we focus on elements that are crucial to determining the intrinsic excitability of neurons in the CNS, the voltage gated ion channels (VGICs). VGICs as well as being important for physiological function are critical in producing hyperexcitability such as that associated with seizure discharges. Many drugs routinely used in the clinical setting, as well as several novel experimental drugs, have shown interactions with VGICs that underpin, at least in part, their anticonvulsant action. We review the physiological roles of voltage gated ion channels that are selective for sodium, potassium and calcium conductance and attempt to highlight their role in the pathology of epilepsy. This is supplemented by the mechanisms of drug action at these important anticonvulsant targets for classical and clinically relevant compounds (e.g. phenytoin, ethosuximide) as well as some important second generation drugs (e.g. gabapentin, levetiracetam) and novel experimental agents (e.g. retigabine, losigamone, safinamide). We also briefly discuss the urgent need for new drugs in this arena and the potential of combinatorial methods and recombinant screening to identify leads.
- ArticleLanas A.Curr Top Med Chem. 2005;5(5):441-2.