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Valdecoxib is a second-generation COX-2 inhibitor, developed as a follow-up to celecoxib for the oral once-daily treatment of osteoarthritis, adult rheumatoid arthritis and menstrual pain. The first step for the preparation of valdecoxib is the conversion of deoxybenzoin to Its corresponding oxime. Deprotonation of this oxime with butyl lithium followed by condensation with ethyl acetate gave the corresponding isoxazoline, which, after treatment with chlorosulfonic acid and reaction with...
Ch
Sivelestat is an acyi enzyme inhibitor of neutrophil elastase, developed as an injectable formulation for the treatment of acute lung injury associated with systemic inflammatory response syndrome. A neutrophil predominant inflammation associated with excessive release of human neutrophil elastase (HNE) from azurophilic granules is capable of damaging both the lung parenchymal cells and the extracellular matrix allowing an alveolar capillary barrier disruption. Sivelestat is a...
Advances In Agents Of Known Mechanism Of Action
Allvlamines - The allylamine mechanism of action reversibly inhibits squalene epoxidase, a key enzyme in ergosterol biosynthesis, resulting in accumulation of intracellular squalene, which blocks new sterol synthesis and diminishes membrane ergosterol content. The best-known compound is terbinafine (Lamisil, 19) that is available as both an oral formulation and a topical preparation for the treatment of dermatophyte infections (37,38). Terbinafine has good antifungal activity against C....
Ibd
Anti-TNFa Biologicals - The first biological approach to be approved for the treatment of steroid-refractory severe CD and fistulating disease was the chimeric anti-TNFa mAb, Infliximab (44). Even, as an i.v. infusion, this agent has had remarkable market penetration and has recently been additionally indicated as therapy for the maintenance of remission. However, there are a number of long term safety concerns associated with Infliximab, both in terms of the high degree of immunogenicity it...
Nonion Channel Mechanisms
Due to the overwhelming number of emerging neuropathic pain targets, it became necessary to focus and restrict the current review primarily to ion-channel classes of therapeutics. Other targets, some equally compelling as those highlighted above, are also emerging. Recent advances in the area of G-protein coupled receptors (GPCRs) offer additional strategies for the design of effective agents. Galanin, muscarinic, prostanoid, adenosine, cannabinoid, opioid, neuropeptide Y, cholecystokinin,...
Dna Polymerase Inhibitors
The 8-hydroxy-1,6-naphthyridine based INSTI's led to the N-benzyl carboxamide L-870,810 (23), a very potent antiviral agent with an IC95 0.019 xM against wild type virus (53,54). This compound entered phase I clinical trials in 2002 (55). Proof of concept studies with the related naphthyridine amide L-870,812 (24) demonstrated a significant antiviral effect in a group of rhesus macaques infected with the simian-human chimeric virus SHIV 89.6p. Macaques receiving a 10 mg kg1 dose of L-870,812...
Section Iv Cancer And Infectious Diseases
Plattner, Chiron Corp Emeryville, CA Chapter 17. Progress in Antifungal Drug Discovery Mark B. Anderson, Terry Roemer, and Robyn Fabrey Elitra Pharmaceuticals 3510 Dunhill Street, San Diego CA 92121 Introduction - The incidence of opportunistic fungal infections such as Aspergillus species, Candida spp. (C. albicans and others) and Cryptococcus neoformans has been increasing worldwide despite active research programs devoted to the discovery and development of novel antifungal...
F
TAK-456 (25) showed strong in vitro activity against clinical isolates of Candida spp., Aspergillus spp., and C. neoformans-, however, activity was less for C. glabrata. TAK-456 inhibited sterol synthesis of C. albicans and A. fumigatus by 50 at 3 to 11 ng mL (59). Ravuconazole (BMS-207147 ER-30346, 26), is an orally available broad spectrum agent that recently completed a double-blind, randomized, placebo-controlled Phase l ll clinical trial. At a dose of 200 mg once daily, it is a safe and...
Posttranscriptional Gene Silencing
The key processes of gene silencing can vary widely not only in timing but also in location - nucleus or cytoplasm - and they can be either reversible or permanent. Clearly processes affecting DNA, such as methylation, imprinting and paramutation, occur in the nucleus (17). Such mechanisms are for the most distinct from RNAi even though RNAi-like mechanisms in the nucleus have been recently uncovered. Indeed a series of remarkable observation in plants and yeast implicates an RNAi-like...
Beyond Kinases Purine Binding Enzymes as Cancer Targets
Duhl and Stephen D. Harrison Chiron Corporation, Emeryville, CA 94608 Introduction - The ideal target for small molecule drug discovery is one that is essential for the disease state, yet non-essential for normal tissues. From a practical perspective, the ideal class of target has a proven track record of drugability, i.e. a history of the identification of agonists or antagonists with acceptable pharmaceutical properties. One recently emerged class of drugable targets is...
Section I Central Nervous System Diseases
Robertson, Pfizer Global Research & Development Ann Arbor, MI 48105 Chapter 1. Current and Emerging Opportunities for the Treatment of Neuropathic Pain John A. Butera and Michael R. Brandt Wyeth Research CN 8000, Princeton, NJ 08543-8000 Introduction - Neuropathic pain is characterized by abnormal pain sensations, including spontaneous pain, hyperalgesia (i.e., increased sensitivity to a noxious stimulus) and allodynia (i.e., increased sensitivity to a non-noxious stimulus)...
Utility Of Snps In Medicine And The Pharmaceutical Industry
Understanding the link between genetic variation and phenotype variation is the foundation for the science of human genetics. Human genetic research has lead to the discovery of more than 1,200 genes that cause rare Mendelian diseases. The genetic effect in these diseases is very strong and in the majority of them contributes to 100 of the disease. However, the majority of human mortality and morbidity is due to diseases that do not fit a clear Mendelian inheritance pattern. These diseases have...
Antibacterial Treatment of Community Acquired Respiratory Tract Infections
Wagman and Mary Lee MacKichan Chiron Corporation, Small Molecule Drug Discovery, 4560 Horton Street, M S 4.5, Emeryville, CA 94608-2916 Introduction - Community-acquired respiratory tract infections (CARTIs) represent one of the most globally prevalent classes of infection. Acute RTIs account for approximately 75 of all antibiotic prescriptions and 20 of all medical consultations (1). Community-acquired upper respiratory tract infections (CAURTI) (pharyngitis tonsillitis, laryngitis,...
Prototypic Victims Of Enzyme Induction
The consequences of administering strong enzyme inducers to human subjects (e.g. rifampicin and phenytoin) have been well documented, and several are described here to highlight the clinical issues associated with potential reductions in clinical efficacy. These include oral contraceptives (risk of conception), calcium channel blockers (loss of blood pressure control), anti-HIV drugs (lack of suppression of HIV replication), and several anti-cancer agents (reduced anti-tumor activity ). Oral...
Assays To Monitor For Enzyme Induction In Vitro
Our current understanding of the mechanisms of gene regulation offers opportunities to develop assays to evaluate each step of the gene regulation cascade. These include nuclear receptor, mRNA, protein, or enzyme activity assays, and examples of each are either referenced or described below. An enzyme induction assay based on human hepatocyte preparations using enzyme activity as the readout is still considered by many to be the assay of best practice. An assay based on apoprotein detection is...
Mch2
Chemotherapy-induced nausea & emesis Irritable bowel syndrome inflammatory bowel disease +Chronic obstructive pulmonary disorder No further development activity reported Chemotherapy-induced nausea & emesis Irritable bowel syndrome inflammatory bowel disease +Chronic obstructive pulmonary disorder No further development activity reported NK Receptor Antagonists - The mammalian tachykinins substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) bind and activate NK receptors with SP...
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Amrubicin was launched in Japan as an injectable preparation for the treatment of non-small and small-cell lung cancers. Amrubicin, a completely synthetic anthracycline derivative, mediates its growth inhibitory action via topoisomerase II inhibition. It is activated in vivo by the formation of its 13-OH metabolite, amrubicinol, via reaction with carbonyl reductase. In contrast to doxorubicin and daunorubicin whose metabolites are inactive in the blood, amrubicinol is 10-100 fold more cytotoxic...
Role Of Bradykinin B1 Receptors In Pain
A large body of evidence has been developed over the past decade supporting a role of B1 receptors in mediating various pain responses. The inducible nature of the B1 receptor has led to the belief that B1 receptors are most relevant for pain during longer term inflammatory conditions, while B2 receptors are important mediators of acute pain and the early inflammatory response (3-6). This hypothesis was initially proposed based on studies comparing effects of the peripheral administration of...
Inhibitors Of West Nile Virus And Papilloma Virus
Inhibitors of West Nile Virus (WNV) - The geographical scope of the mosquito-borne West Nile virus outbreak in the US broadened considerably in the summer of 2003 extending to almost all states and causing over 2,500 cases of encephalitis and 230 deaths (157,158). The virus presents several conventional proteins as targets suitable for intervention including the NS3 protein, which expresses serine protease, helicase and nucleoside triphosphatase activities, and the NS5 RNA-dependent RNA...
Gsk
First Introduction USA Introduced by United Therapeutics Trade Name Remodulln CAS Registry No 289840-64-4 Molecular Weight 412.51 Treprostinil sodium has been launched for the treatment of pulmonary hypertension. This synthetically designed tricyclic benzindene analog of the natural potent vasodilator prostacyclin has been developed for subcutaneous infusion. Treprostinil sodium can be prepared in a 15 step stereoselective process. It has been suggested that treprostinil sodium acts via the...
The Properties Of Lipid Rafts
Recent evidence indicates that the plasma membrane is not a uniform lipid bilayer but rather contains within it discrete microdomains rich in cholesterol and sphingolipids termed lipid rafts. Several excellent reviews have been published recently describing both the biochemistry and biological function of lipid rafts (1,3-6). Briefly, the outer leaflet of the plasma membrane contains both sphingolipids with highly saturated acyl chains and glycerophospholipids with unsaturated, kinked acyl...
Perspective
Mihaly, S. Sarkar, W.M. Rand, G. Legradi, C.H. Emerson, R.M. Lechan, Endocrinology, 142, 2606 2001 . 8. J. T. Clark, P. S. Kalra, W. R. Crowley, S. P. Kalra, Endocrinology, 115,427 1984 . 9. B. G. Stanley, S. F. Leibowitz, Life Sei., 35, 2635 1984 . 10. M. Egawa, H. Yoshimatsu, G. A. Bray, Am.J.Physiol., 26fi, R328 1991 . 11. J.J. Hwa, M.B. Witten, P. Williams, L. Ghibaudi, J. Gao, B.G. Salisbury, D. Mullins, F. Hamud, C.D. Strader, E.M. Parker, Am.J.Physiol, 277,...
The use of bioisosteric groups in lead optimization
Xiaoqi Chen1 and Weibo Wang2 1Tularik Inc. 1200 Veteran Drive, South San Francisco, CA 94080 2Chiron Corporation, 4560 Horton Street, Emeryville, CA 94608 Introduction - With the rapid advance of the human genome program, high throughput screening HTS and combinatorial chemistry, an unprecedented large number of hits are generated and funneled down to the hands of medicinal chemists at an ever-increasing speed. Additional extensive work is often required to increase the potency or in vitro...
Inhibitors Of Herpes Simplex Virus And Human Cytomegalovirus
The eight human herpes viruses cause a variety of pathophysiological conditions ranging in severity from mild cold sores to life threatening illnesses in immunocompromised patients. While herpes simplex virus HSV types 1 and 2 typically cause localized cold sores and genital herpes, other members of the herpesviridae family can be more problematic. Varicella zoster virus VZV is the causative agent in chicken pox whilst human cytomegalovirus HCMV is particularly difficult for the...
Mc4r Antagonists
The development of selective, high affinity antagonists for MC4R trailed the development of MC4R agonists. Several structure-activity studies were reported on the lactam SHU9119, an analog of aMSH and a nonselective MC3R MC4R antagonist 75,76 . Analogs of SHU9119 with altered lactam ring sizes, amino acid substitutions and or chirality changes in the active core were prepared in an effort to optimize receptor subtype selectivity 77-79 . Replacement of His6 with 1-amino-1-cyclopentane carboxylic...
Ab Aggtca n AGGTCA
Coactivators are linker proteins that recognize the activated PPAR receptor as well as the transcription machinery and thus are also required to turn on gene transcription 4-6 . In some cases, negative regulation also occurs through the binding of corepressors 7 . Thus gene transcription is regulated by a number of proteins and ligands in a very sensitive manner that might differ depending on the tissue. PPARa, first cloned in the early 1990's, plays an important role in lipid metabolism. It...
Reflex Control Of The Lower Urinary Tract
Supraspinal Micturition Reflex - Figure 1 shows the normal supraspinal, parasympathetic micturition reflex responsible for determining when micturition occurs under normal conditions without underlying pathology . This reflex is initiated by stretch receptors in the detrusor muscle the smooth muscle of the bladder body which passively stretches during filling and actively contracts during micturition. The stretch receptors are terminal specializations of thinly myelinated AS afferent fibers...
Section Vii Trends And Perspectives
Doherty Pfizer Global Research amp Development Chapter 33 . To Market, To Market - 2002 C cile Boyer-Joubert, Edwige Lorthiois and Fran ois Moreau Pfizer Global Research amp Development Fresnes, France A significant increase in the number of new therapeutic chemical and biological entities was observed in 2002 compared to 2001 33 vs 25 1-6 . From the 31 NCEs and 2 NBEs launched on the market last year, the US market saw 17 new entities introduced, the Japanese market 8 and the...
Pharmacophorebased Virtual Screens
For our purposes, a pharmacophore is defined as the spatial arrangement of a minimal set of discriminating molecular features necessary to characterize the biological activity of a given system. Molecular fragments or macro classes such as hydrogen-bond acceptor donor sites, ionized, or hydrophobic groups, can represent each of these features in three-dimensional space. A variety of techniques can be used to develop a pharmacophore model ranging from simple hypothesis generation via manual...
Mc4r Agonists
Peptidvl MC4R Agonists - All endogenous ligands contain a conserved peptide fragment - His6-Phe7-Arg8-Trp9 a-MSH numbering - which has been identified as the active core or message sequence responsible for interaction with the melanocortin receptors. a-MSH is a 13 amino acid peptide agonist at all melanocortin receptors. Structure-activity studies identified Nle ,DPhe7 a-MSH NDP-a-MSH, MT-I - a more potent and enzyme-resistant analog with D-Phe substitution at position 7 23 . This and its...
Treatment Of Constipation
Rationale for IBS and non-IBS constipation - According to ROME II criteria, Irritable Bowel Syndrome IBS is subdivided into 3 major subsets of patients exhibiting either diarrhea IBS-D , constipation IBS-C or alternating constipation and diarrhea IBS-A representing 30, 50 and 20 of all IBS patients respectively. However chronic constipation may occur in patients not exhibiting abdominal pain and consequently not included in IBS-C patients. Chronic constipation as IBS-C is often associated with...
Inhibitors Of Hepatitis B And C Virus
Inhibitors of Hepatitis B Virus HBV - Adefovir dipivoxil Hepsera 1 was approved in the US for the treatment of HBV on September 20th, 2002 and in the European Union on March 11th, 2003, providing a second small molecule antiviral to add to lamivudine 3TC and the injectable protein IFNa as the only approved agents for treating HBV infection. Adefovir is an effective inhibitor of 3TC-resistant HBV caused by the rtM204l and rtL180M rtM204V mutations in the reverse transcriptase 2 and resistance to...
