A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability to liberate parent drug 1 in in vitro and in vivo systems. The l-alanine prodrug 8 (also known as brivanib alaninate/BMS-582664) was selected as a development candidate and is presently in phase II clinical trials.
The hypoxic state in a solid tumor refers to the internal hypoxic environment that appears as the tumor volume increases (the maximum radius exceeds 180-200 microns). This state can promote angiogenesis, destroy the balance of the cell’s internal environment, and lead to resistance to radiotherapy and chemotherapy, as well as poor prognostic factors such as metastasis and recurrence. Therefore, accurate quantification, mapping, and monitoring of hypoxia, targeted therapy, and improvement of tumor hypoxia are of great significance for tumor treatment and improving patient survival. Despite many years of development, PET-based hypoxia imaging is still the most widely used evaluation method. This article provides a comprehensive overview of tumor hypoxia imaging using radionuclide-labeled PET tracers. We introduced the mechanism of tumor hypoxia and the reasons leading to the poor prognosis, and more comprehensively included the past, recent and ongoing studies of PET radiotracers for tumor hypoxia imaging. At the same time, the advantages and disadvantages of mainstream methods for detecting tumor hypoxia are summarized.
The
discovery, development, and optimization of an Ullmann–Goldberg–Buchwald
coupling reaction is described. This complex process represents a
key transformation in the development of a commercially viable synthesis
of the HIV attachment inhibitor prodrug BMS-663068. In this reaction,
high regioselectivities were obtained for the coupling of a 1,2,4-triazole
and a 7-bromoazaindole, preparing BMS-626529, the antepenultimate
in good yield and quality. Key challenges associated with developing
commercially viable conditions for this copper-mediated coupling include
achieving the desired level of regiochemical control, identifying
robust isolation conditions and controlling residual copper levels
in the isolated product.
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