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All rights of reproduction in any form reserved. The function of the brain is extremely dynamic. Neonate, adult and aged brains are morphologically and phenotypically very distinct. Diseased brain can be very different from the 'normal', healthy brain. Transmitters and receptors present during development disappear in adult brain, while receptors change in number and function due to disease and nervous system trauma. Mechanisms to sustain brain homeostasis,...

Inhibitors

The search for antiangiogenic agents for the treatment of cancer has been an area of intense research for the last decade. Several approaches have been investigated leading to several clinical trials of new chemotherapeutics (71). One such area has been the investigation of inhibitors of vascular endothelial growth factors and their receptors. Most notably, ATP-competitive inhibitors of VEGFR-2 (KDR) have undoubtedly attracted the most attention throughout the pharmaceutical industry. VEGF is a...

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Intense interest has been placed on inhibitors of the EGFR (erb-B1), due to the involvement of growth factors in this gene family in the development and progression of cancer. These growth factors bind to the extracellular domain of the EGFR resulting in receptor dimerization and subsequent activation of the intracellular tyrosine kinase domain by the process of autophosphorylation on several, key tyrosine residues. Various transducing molecules bind to the newly formed high affinity binding...

Herpes And Related Viruses

Since many of the agents utilized for this disease are nucleosides and nucleoside analogs, most find use in other related herpes therapy such as cytomegalovirus (CMV) and varicella-zoster virus. Like many of the other nucleoside analogs, penciclovir (33), one of the first topical agents to exhibit activity during early or late stage disease, is being studied via a series of prodrug forms to increase the poor oral bioavailability. Another set of related viruses, human herpesvirus 6 and 7 (HHV-6,...

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The olomoucine analog CGP-79807 (9) is under preclinical evaluation (40). A related series of diaminocyclohexyl purines 10 that are substituted by a biphenyl methyl group at N6 are reported as potent cytotoxic agents in cells(ca. 1 nM), despite ca. 1 (iM activity against the isolated cdk2 cyclin E complex (41). Compound 1_1 is currently in preclinical development as a 50 nM inhibitor of cdk2 (42). Bicvclic ATP Mimetics Indolinones - The indolinone template is commonly found among inhibitors of...

Inhibitors Of Cyclin Dependent Kinases

Mechanistic rationale - In addition to epidemiological and genetic evidence that restriction point control is aberrant in essentially all human cancer, there is growing mechanistic support for the potential of cdk2 inhibitors in the treatment of proliferative disease. Phosphorylation of RB by cdk4 cylin D and cdk2 cyclin E complexes frees transcription factors of the E2F family and initiates the transcription of a host of genes that are critical for the cell to pass the G1 S boundary....

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BMS-247243 (18) is a novel parenteral cephalosporin derivative with excellent activity against Gram-positive bacteria (76-82). BMS-247243 has good potency against MRSA, with an MICgo of 4 ng mL. This compound was identified from a series of analogues bearing lipophilic substituents at the C-7 position. Introduction of the additional carboxylate on the C-7 side-chain gave improved solubility and safety in preclinical testing. BMS-247243 is efficacious in a variety of infection models....

Therapeutic Potential Of Dppiv Inhibition

With its unique substrate specificity and localization as an ectoenzyme at the plasma membrane, DPP-IV plays an important role in initiating N-terminal degradation of a number of neuropeptides, peptide hormones and chemokines with N-terminal Xaa-Pro and Xaa-Ala. However, most studies reporting cleavage of synthetic peptide substrates are under in vitro conditions, making predictions of a physiological role for DPP-IV in the control of biological activity of most substrates speculative. A number...

Exploiting The Genome Of The Brain

A large number of chromosomal loci containing susceptibility genes potentially involved in disease etiology as well as gene candidates for schizophrenia, BPAD, etc. have been identified 25,26 . Validation of these is based on epidemiological data showing a significant genetic contribution to disease etiology. Interactions between more than one susceptibility gene and environmental risk factors the envirome 27 clearly contribute to disease incidence, the norm of reaction factor -indicating that...

Summary And Future Directions

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