Anorexigenic Receptors

Reduction of food intake is mediated by anorexigenic receptors, presumably through increasing satiety. For the most part, these receptors are compelling anti-obesity drug targets since they actively reduce food intake. However, these targets typically require an agonist approach, presenting a more demanding drug discovery challenge. Moreover, issues of tolerance and desensitization are major concerns for agonist therapy. The two anorexigenic systems discussed in this report are the serotonin...

5HT2C Receptor Modulators Progress in Development of New CNS Medicines

Fitzgerald and Michael D. Ennis Structural, Analytical, and Medicinal Chemistry and CNS Discovery Research Pharmacia Corporation, Kalamazoo, Ml 49007 Introduction - The decades-old discovery of serotonin (5-HT) as a vasoconstrictor and prominent neurotransmitter (1-3), has since sparked an intense research effort that has elucidated the diverse roles of 5-HT in mediating sensory, motor, and behavioral processes. Although 5-HT-containing neurons comprise only a rather circumscribed...

Intracellular Signaling Targets for Cancer Chemosensitization

Harrison Chiron Corporation, Emeryville, CA 94608 Introduction - Chemotherapy and radiation exposure are the major options for the treatment of cancer. The application of both of these therapies is limited by severe adverse effects on normal tissues and the frequent development of tumor cell resistance. It is therefore highly desirable to improve the efficacy of these treatments without increasing the toxic side effects and to counteract the resistance mechanisms...

Emerging Microtubule Stabilizing Agents for Cancer Chemotherapy

Myles Kosan Biosciences, Inc. 3832 Baycenter Place, Hayward, CA 94545 Introduction - The discovery of the potent anti-cancer properties and subsequent elucidation of the mechanism of action of paclitaxel firmly established this compound as a leader in the treatment of difficult cancers. In addition, the unusual mechanism of action of paclitaxel, the stabilization of microtubules, distinguished it from other microtubule-binding agents, such as the vinca alkaloids, that act by...

Disease Biosimulation

Cardiac Arrhythmia - Biosimulation of cardiac electrophysiology has a long history and has advanced in close collaboration with experiments. Realistic differential equation models have been constructed for almost every type of cardiac cell, incorporating a host of ion channels, exchangers, pumps, and dynamically regulated intracellular pools of sequestered calcium (32-38). Recently, biosimulation has been used to better understand the cause of a cardiac arrhythmia, called long-QT syndrome,...

Info

Eletriptan, the seventh member of the triptan class of antimigraine drugs was launched last year in Switzerland for the acute treatment of migraine. The 5-step synthesis of this conformationally restricted analog of sumatriptan involves the deprotonation of 5-bromoindole with Grignard reagent at the position C3 followed by a condensation with N-Cbz-D-proline acid chloride to afford the key Cbz-D-prolyl intermediate. After reduction with UAIH4, the sulfone moiety was introduced in postion 5 by a...

Fc Receptor Structure and the Design of Antiinflammatories New Therapeutics for Autoimmune Disease

Powell, Paul A. Ramsland and P. Mark Hogarth Austin Research Institute Austin and Repatriation Medical Center, Studley Road, Heidelberg, Victoria 3084, Introduction - Inflammation caused by immune complexes in the blood vessels (vasculitis), the kidney (glomerulonephritis) and in the joints (arthritis) is a major cause of morbidity in autoimmune diseases. It is also one of the major mechanisms of tissue destruction in diseases including rheumatoid arthritis...

Antagonists of VLA4

Blediger, and Peter Vanderslice Texas Biotechnology Corporation 7000 Fannin, Houston, TX 77030 Introduction - Integrins are a family of heterodimeric cell surface receptors consisting of an a and a p subunit (1). Different a and p subunits can associate to yield a family of no less than 23 members each with a distinct pattern of ligand selectivity. The integrin a4pi is also known as VLA-4 (very late antigen-4). VLA-4 is expressed on the surface of most leukocyte or...

Attention Deficit Hyperactivity Disorder Pathophysiology and Design of New Treatments

Robertson and Lawrence D. Wise Pfizer Global Research and Development Ann Arbor, Ml 48105 Introduction - Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in children, and estimates of its incidence generally range from 3-5 however, much higher incidences are sometimes cited (1,2). The actual incidence is a controversial subject, and recent studies suggest some of the differences in reported rates are based upon stringency of criteria...

Section Ii Cardiovascular And Pulmonary Diseases

Greenlee, Schering Plough Research Institute, Kenilworth.NJ Chapter 5 Recent Advances in Pulmonary Hypertension Therapy Russell A. Bialecki AstraZeneca Pharmaceuticals 1800 concord Pike, Wilmington, DE 19850-5437 Introduction - Pulmonary hypertension is functionally defined as inappropriately high pulmonary arterial pressure for a given level of blood flow through the lungs. Normally, the pulmonary circulation is a low-pressure, high-flow system. Pulmonary artery systolic...