Inosine Monophosphate Dehydrogenase Consideration of Structure Kinetics and Therapeutic Potential

Raybuck Vertex Pharmaceuticals, Cambridge, MA 02139 Introduction - Inosine 5'-monophosphate dehydrogenase (IMPDH, E.C.1.1.1.205) catalyzes the NAD dependent oxidation of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate (XMP) and is the rate-limiting enzyme of the de novo pathway for guanine nucleotide biosynthesis. Guanine nucleotides are essential to the cell for RNA and DNA synthesis, intermediates in signaling pathways, and as energy sources for...

Present Issues And Future Prospects

The development of protein fragments, in particular, as anti-angiogenic therapeutics has been the focus of great attention. Issues for these molecules still include reproducibility of in vivo results and production of reproducible lots of material for clinical trials. The recently initiated clinical trials of endostatin may provide the data on whether this approach will live up to its preclinical publicity. Generally, the key issues facing the anti-angiogenic approach to cancer therapy is the...

Recent Advances in Development of Novel Analgesics

Lynch and Michael F. Jarvis Abbott Laboratories, Abbott Park, IL 60064 Introduction - Nonsteroidal anti-inflammatory drugs (NSAIDs, e.g. aspirin, ibuprofen and naproxen), opioids (e.g. morphine) and a variety of adjuvant agents (e.g. tricyclic antidepressants, lidocaine and certain anticonvulsant agents) have been mainstays of pain therapy for decades. All these agents suffer from drawbacks in clinical use. The NSAIDs are associated with gastrointestinal side...

Neural Regulation Of The Cough Reflex

Afferent Mechanisms of the Cough Reflex - Coughing is elicited by stimulation of specialized sensory nerves in the airways. A variety of different stimuli including airway inflammation, chemical irritants (e.g. capsaicin) and mechanical stimuli can trigger coughing in humans and animals. The polymodal sensory nerves that are prominently involved in neural regulation of cough are myelinated A8 rapidly adapting receptors (RAR) and unmyelinated bronchial and pulmonary C-fibers (8). Their nerve...

Attachment Of Pc To Filarial Molecules As A Target For Chemotherapy

Targeting PC with respect to drug development - The immunomodulatory properties of PC appear to be important in allowing survival of filarial nematodes and for this reason the synthesis of PC-containing molecules might represent an important new target for chemotherapy. Certainly, new drugs are urgently required for treatment of filarial nematodes. With this in mind, it was decided to investigate the mode of attachment of PC to filarial nematode proteins. PC is attached to filarial nematode...

Recent Advances in Therapeutic Approaches to Type 2 Diabetes

Wagman2 Exelixis, Inc.1, South San Francisco, CA 94080 Chiron Corporation2, Emeryville, CA 94608 Introduction - Diabetes mellitus is the only non-infectious disease designated as an epidemic by the World Health Organization (1). The prevalence of all types of diabetes is estimated to be 2.3 of the world's population, with the number of diabetics increasing by 4-5 per annum. It is projected that as many as 40-45 of persons aged 65 or older have either Type 2 diabetes...

Mmp Inhibitors In Clinical Trials For Cancer

A third study with 29 is focused on patients with the least aggressive cancers. Two of the four trials due to be reported in 2000 involve patients with small-cell lung cancer. These patients have already responded to chemotherapy, so their tumor burden has been reduced to some extent. The other two studies are for patients with glioblastoma and ovarian cancer, both of which are aggressive cancers with high tumor burdens. Prinomastat (AG-3340, 30) is being developed for the treatment of cancer...

Info

Glucose absorption, 211 glucose tolerance, 213 glucose-6-phosphatase, 214 glycogen phosphorylase, 213 glycosidase inhibitors, 217 GM 237254, 161 gp120, 181 gp41, 182 GPCR agonists, 293, 294, 295, 296, 297 Gpllb llla antagonist, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 115, 118 Gpllb llla receptor, 103 GPIIIa polymorphisms, 112 gram-negative, 137,140,141,142, 143 Group I metabotropic glutamate receptor agonists, 2, 4, 5, 6 Group II metabotropic glutamate receptor agonists, 3, 4, 6...

Chemistry Of Small Molecule Cetp Inhibitors

As a transfer protein, CETP presents several unique challenges for inhibitor design. Access to potent (nM) inhibitors based on transition-states is unavailable, since there is no chemistry of catalysis. An ideal drug candidate would likely be specific for CETP and not disrupt the integrity of other lipoproteins. While the available biochemical data indicate that human CETP contains independent binding sites for neutral and phospholipids (7), the exact stoichiometry, affinity, and...

Ci

Colestimide was launched in Japan for the treatment of hyperlipidemia and hypercholesterolemia. It is a newly developed methyl imidazole-epichlorhydrin copolymer this anion exchange resin works as a powerful bile acid sequestrant, thus increasing the rate of conversion of cholesterol to bile acids in the liver which may lead to enhancement of the rate of LDL removal. In animal models and humans, Colestimide proved to be more potent than cholestyramine and seems to be better tolerated. It...

H

CAS Registry No 130112-42-4 Molecular Weight 330.45 Mivotilate is an orally-active hepatoprotective agent introduced last year for the treatment of liver cirrhosis and hepatitis-B infection. It is a dithietanylidene malonate analogue of malotilate and is without the haemotological adverse effects associated with the latter. Mivotilate can be obtained by partial saponification of the corresponding diisopropylmalonate, conversion of the acid function into mixed anhydride then to the amide with an...

Permeability Models In Early Discovery

Although a variety of models (subcellular fractions, cell monolayer models, isolated intestinal tissue, intestinal perfusion, transfected cell lines) are available, cell monolayer models and rat intestinal perfusion techniques are the most commonly used systems in the pharmaceutical industry today(30,31). Cell monolayers - These models consist of cells grown on permeable inserts. Transport of compound across the cell monolayer can be used to quantitate the permeability of NCEs in a rapid...

O T ocro

Conclusion - Clinical data with linezolid illustrate the potential for oxazolidinones to be effective weapons against gram-positive bacteria in humans. The importance of their activity against drug resistant strains of gram-positive pathogens is highlighted by a backdrop of escalating bacterial resistance. New analogues have been found with increased gram-positive potency and also activity against fastidious gramnegative organisms. The relative ease with which the oxazolidinones can be prepared...

Azithromycin And Clarithromycin Update

The median MICs (minimum inhibitory concentrations) against Mycobacterium-avium-M. intracellulars complex was found to be 8 ng ml for azithromycin and < 2 ng ml for clarithromycin (55). The MIC value for clarithromycin against 46 strains of M. ulerans ranged from 0.125-2 ng ml at pH 6.6 and from 0.125-0.5 ng ml at pH 7.4 (56). The MICgo value for clarithromycin tested against Actinobacillus actinomycetem-comitans is < 2 ng ml (57). The susceptibility of Coxiella burnetii, the etiologic...

Integrating Information For Risk Analysis

The goal of early-ADME profiling is to answer first-cut questions Will the NCE be absorbed Can the NCE be formulated readily Will metabolic liability limit systemic exposure ADME risk analysis combines experimental and derived parameters with assigned limits. For example, in order to deliver 1 mg kg dose and assuming moderate permeability of 10 to 20x 106 cm s, it would be necessary to achieve a solubility concentration of at least 50 microg mL in the Gl tract (95). Examination of the...

Enhancers Of Insulin Action

Non-thiazolidinediones (non-TZDs) - There are now a variety of potent non-TZD PPARy ligands which exhibit antidiabetic activity in vivo, including GW-1929 26 (61,62), GI-262570 27 (63), GW-409544 (64), JTT-501 28 (65),and YM-440 (66). GW-1929 is approximately 100-fold more potent in rats than troglitazone in glucose lowering based on serum drug levels (67). The (S)-enantiomer of SB-219994 29 is considerably more potent and efficacious than its antipode (68). The phenylacetic acid derivative 30...

Novel Macrolides To Overcome Bacterial Resistance

Oerskovia Species

Macrolide derivatives having activity against erythromycin resistant S. pyogenes were first reported in 1989 (79). Several 11,12 carbamate clarithromycin analogs and several 11,12-carbonate erythromycin analogs with additional modifications at the 4 position of the cladinose were found to be active against both inducible and constitutive-resistant S. pyogenes . Based on this initial discovery, recent chemical modifications of erythromycin have generated several new classes of macrolide...

Chemokines Targets for Novel Therapeutics

Low1, Kenneth Carson2 and Gregory J. LaRosa2 1 Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Departments of Medicinal Chemistry and Molecular Biology, Ann Arbor, Ml 48105 Millennium Pharmaceuticals Inc., 75 Sydney Street, Cambridge, MA 02139 Introduction - The trafficking of pro-inflammatory leukocytes is regulated by a complex, multi-step process involving cell-cell adhesion, protein interactions between leukocytes and vascular...

Arglabin Prodrug

Country of Origin US Originator Vertex Pharm First Introduction US Introduced by Glaxo Wellcome Trade Name Agenerase CAS Registry No 161814-49-9 Molecular Weight 505.64 Country of Origin Kazakstan Originator NuOncology Labs First Introduction Russia Introduced by NuOncology Labs Trade Name CAS Registry No 84692-91-1 Molecular Weight 246.31 Arglabin is a new antineoplastic agent launched in Russia for the treatment of a variety of cancers. It is a sesquiterpene gamma-lactone extracted from...