Hdac Inhibitors As Anticancer Agents

HDAC inhibitors bear great potential as new drugs because of their ability to modulate transcription, and are endowed with cytodifferentiating, antiproliferative and apopto-genic properties 9 . Furthermore the anticancer activity of HDAC inhibitors may be mediated in part by the inhibition of angiogenesis, since it was shown recently that TSA, 1, specifically inhibited hypoxia-induced angiogenesis by reducing the expression of genes required for angiogenesis 10 . Several structural classes of...

Arthritis

Collagen-induced arthritis (CIA) in rodents is an accepted model for rheumatoid arthritis (RA) in man. Two injections of type II collagen separated by 21 days results in the onset of a classic Th1 lymphocyte driven arthritis inflammation becomes apparent 5-10 days after the second dose of collagen. The ability of simvastatin to modulate the disease process was tested in both a prophylactic protocol, where the drug treatment started before the second dose of collagen, and in a therapeutic...

Central Nervous System Diseases

Section Editor David Wustrow, Pfizer Global Research & Development, Ann Arbor, Michigan 1. Attention Deficit Hyperactivity Disorder Pathophysiology Shelly A. Glase and David J. Dooley, Pfizer Global Research & Development, Ann Arbor, Michigan 2. Ionotropic GABA Receptors as Therapeutic Targets for Memory Mary Chebib1, Jane R. Hanrahan1, Kenneth N. Mewett2, Rujee K. Duke1, 2 and Graham A.R. Johnston2, The Adrien Albert Laboratory of Medicinal Chemistry 1Faculty of Pharmacy & 2Department...

Azelnidipine Antihypertensive [2931

Country of origin Originator First introduction Introduced by Trade name CAS registry no. Molecular weight Japan Sankyo Japan Sankyo Calblock 116574-11582.66 Azelnidipine, a member of the 1,4-dihydropyridine class of L-type calcium channel blockers with a slow onset profile, was marketed in Japan for the treatment of hypertension. Azelnidipine is synthesized via the condensation of iso-propyl 2-(3-nitrobenzylidene)acetoacetate with acry-late. The diamino acrylate intermediate is prepared from...

Clinical Advances With Combinations Of Antimetabolites

Anti-cancer agents are rarely given singly, as combinations of drugs have proven to be far superior to single agent therapy for a variety of cancers. Antimetabolites are no exception they have been combined with other antimetabolites and with other chemotherapeutic agents. The goal of combination therapy is to find agents whose activities are synergistic, i.e., a regime where the combined effect is greater than what would be expected from the sum of the two individual agent's activities, and...

Dementia

Epidemiological studies have suggested that statin treatment in man may be beneficial in the treatment of dementia 115-119 . This has been extensively reviewed in previous years 120 . As with all epidemiological data which relies on historical data, the answer is not clear-cut and a number of prospective studies are now underway. An added complexity for analysing trial data for a role of statins in treating dementia is their variable penetration across the blood brain barrier. The etiology of...

Nonldl Cholesterol Lowering Actions Of Statins

The efficacy of statins in lowering serum LDL cholesterol is well-recognised 2-4 . The widespread clinical use of statins has led to observations that statins have additional effects not explicable through their primary role of lowering serum LDL cholesterol. Initial clinical trial data in patients with hypercholesterolemia indicated beneficial effects of statins on cardiovascular parameters beyond that expected for their ability to directly lower LDL cholesterol 3,27-31 . There is now...

Prodrugs Of Nucleosides The Ribose Ring

The dominant prodrug strategy adopted on the ribose ring involves appending carboxyl groups, e.g. esters, carbonates and carbamates, to the ribose hydroxyl groups, in order to improve drug exposure and oral bioavailability. The prodrug can block unwanted metabolic pathways, increase log D, and improve permeability. Additionally, some prodrugs, e.g. amino acid esters, can take advantage of in vivo transporter systems. Peptidases, esterases and other hydrolases in the host catalyze the release of...

Agomelatine and derivatives

Agomelatine 7 is a potent agonist at melatoninergic receptors. It shows a high affinity for cloned human melatonin receptor MT1 and MT2 sub-types (K 61 , and 268 pM, respectively). The affinity of agomelatine at melatonin receptors is comparable to that of melatonin (K 85 and 263 pM, respectively). Agomelatine also shows affinity (IC50 270 nM) for human cloned serotonin-2C (5-HT2C) receptors, and acts as an antagonist at this receptor subtype 63 . Agomelatine has shown antidepressant activity...

Introduction

In host defense, the complement system of blood-borne proteins initiates a series of cellular and inflammatory responses to divergent stimuli. These can vary from infectious agents (e.g., bacteria, viruses and parasites) to biochemical, chemical and physical injury 1 . Excessive activation of the complement system in man results in elevated C5a, a glycosylated 74-amino acid protein that is associated with several acute and chronic clinical situations or disease states. Due to the...

Synthetic Melatonin Agonists

Melatonin from the pineal gland was recently reported to be distributed to the brain via the cerebrospinal fluid 49 . Exogenously administered deuterated melatonin has low absolute bioavailability in man (1-37 ) due to first pass metabolism and a short half life reported to be approximately 40 min 50 . The shortcomings of exogenously administered melatonin as a drug have led to the search for improved synthetic melatonin agonists. Some of the novel synthetic melatonin agonists previously...

Melatonin and sleep

Sleep deprivation and poor sleep quality can reduce cognitive function, memory and negatively affect mood 31,32 . Understanding the relationship of melatonin levels to sleep disorders, depression and anxiety has become a topic of considerable recent research and the melatonin receptors MT1 and MT2 have emerged as therapeutic targets of interest 33 . Melatonin's effect on the duration and quality of sleep has been reported in the literature and in a recent clinical trial, the effects of...

Ramelteon

An exciting new drug candidate for the treatment of patients with insomnia and circadian rhythm dysfunction, ramelteon 13 has been reported 52 . It is a high-affinity agonist at MT1 and MT2 receptors with Ki values of 14 and 40 pM, respectively. In a randomized placebo-controlled phase 2 study, ramelteon (4, 8, 16 and 32 mg) significantly reduced the latency to persistent sleep, increased the mean total sleep time, and improved sleep efficiency in patients with chronic insomnia 52 . Subjects...

Peptide Antagonists

The search for potent small C5a peptide antagonists has proven to be a difficult challenge. Initial efforts in protein SAR focused on determining the minimum peptide fragment possessing potent binding affinity. The C-terminal octapeptide was identified as the shortest linear sequence possessing reasonable C5a binding affinity 11 . A major complication associated with C5a antagonists arises from the fact that historically, most C5a receptor active ligands display some partial agonist activity....

Ionotropic Gaba Receptors And Sleep Disorders

The treatment of insomnia is regarded as a developing market for agents acting on GABAA and possibly GABAc receptors. GABA systems are known to play an important role in sleep and positive allosteric modulators of GABAa receptors are widely used to promote restful sleep 36 . The brain lipid oleamide (8, Z-9-octadecenamide) accumulates in the CSF of sleep-derived cats suggesting that it may be an endogenous sleep-inducing factor. Oleamide enhances the effect of GABA on rat cultured cortical...

References

1 The collection of new therapeutic entities first launched in 2003 originated from the following sources (a) CIPSLINE, Prous database (b) Iddb, Current Drugs database (c) IMS R& D Focus (d) Adis Business Intelligence R& D Insight (e) Pharmaprojects. 2 A. I. Graul, Drug News Perspect., 2004, 17, 43. 3 C. Boyer-Joubert, E. Lorthiois and F. Moreau, Ann. Rep. Med. Chem., 2003, 38, 347. 4 P. Bernardelli, B. Gaudilliere and F. Vergne, Ann. Rep. Med. Chem., 2002, 37, 257. 5 B. Gaudilliere, P....