To assess the effect of obesity on CD4 cell counts, we estimated the association of time-updated BMI categories with CD4 changes among 1001 documented HIV seroconverters. During the pre-highly active ...antiretroviral therapy (HAART) era, a higher BMI was associated with less reduction in CD4 cell counts over time. However during the HAART era, obese versus normal weight patients had smaller increases in CD4 cell counts (+69 versus +116 cells, P = 0.01). Lower CD4 cell counts may now be another adverse consequence of obesity.
This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.
Compound 3 (BMS-536924), a novel small-molecule inhibitor of the insulin-like growth factor receptor kinase with equal potency against the insulin receptor is described. The in vitro and in vivo ...biological activity of this interesting compound is also reported.
Transfusion medicine and safety Dodd, Roger; Kurt Roth, W.; Ashford, Paul ...
Biologicals,
04/2009, Letnik:
37, Številka:
2
Journal Article
Recenzirano
Advances in safety of blood transfusion in clinical practice principally relate to preventing transfusion-transmitted infections (TTI). Epidemiological studies of TTI have resulted in the ...development, standardization, and implementation of an expanding array of immunoassays employed worldwide in routine screening of blood donated by voluntary blood donors. Exclusion of infected blood and their donors has remarkably reduced the risk of transmitting HBV, HCV, HIV-1/2, and HTLV-I/II infections. Nucleic acid tests (NAT) using enzymatic amplification of viral gene sequences have augmented the risk reduction in “window period” infections that are undetectable by the serological tests. Improved viral safety of transfusion therapy has led us to recognize the risk of bacterial contamination, especially in platelet concentrates stored optimally at room temperature. Besides the current effort devoted to microbial risk reduction, pathogen inactivation technologies promise reduction of the residual risk of known and emerging infectious agents. The clinical effectiveness of the foregoing measures, international harmonization/standardization of practices and procedures, and continued hemovigilance portend safest possible safety in the clinical practice of blood transfusion.
The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Display omitted
The discovery, ...synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Optimization for JAK family selectivity led to compounds 14 and 21, with greater than 45-fold selectivity for JAK2 over all other members of the JAK kinase family.
Therapeutic development of a targeted agent involves a series of decisions over additional activities that may be ignored, eliminated or pursued. This paper details the concurrent application of two ...methods that provide a spectrum of information about the biological activity of a compound: biochemical profiling on a large panel of kinase assays and transcriptional profiling of mRNA responses. Our mRNA profiling studies used a full dose range, identifying subsets of transcriptional responses with differing EC50s which may reflect distinct targets. Profiling data allowed prioritization for validation in xenograft models, generated testable hypotheses for active compounds, and informed decisions on the general utility of the series.
We have recently identified BMS-345541 (
1) as a highly selective and potent inhibitor of IKK-2 (IC
50
=
0.30
μM), which however was considerably less potent against IKK-1 (IC
50
=
4.0
μM). In order ...to further explore the SAR around the imidazoquinoxaline tricyclic structure of
1, we prepared a series of tetracyclic analogues (
7,
13, and
18). The synthesis and biological activities of these potent IKK inhibitors are described.
We previously reported that 1 (BMS-536924), a benzimidazole inhibitor of the insulin-like growth factor-1 receptor, had demonstrated in vivo antitumor activity. This lead compound was found to have ...potent CYP3A4 inhibition, CYP3A4 induction mediated by PXR transactivation, poor aqueous solubility, and high plasma protein binding. Herein we disclose the evolution of this chemotype to address these issues. This effort led to 10 (BMS-695735), which exhibits improved ADME properties, a low risk for drug−drug interactions, and in vivo efficacy in multiple xenograft models.
A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a ...potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.
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