Breaking into Merck's CCK Patents: the Starting Point of PNB Vesper Life Science to Design and Develop Cholecystokinin(CCK)-Antagonists as Targeted Chemotherapeutics by Eric Lattmann in DDIPIJ in Lupine Publishers
Early anti-cancer research was dominated by the development of
alkylating agents, followed by the discovery of a variety of
anti-metabolites, which were useful anti-viral agents at the same time.
Current anti-cancer drugs are designed towards molecular targets in
order to reduce their toxicity and to enhance the selectivity on the
cancer cells. Within an increasingly growing number of molecular
targets, the cholecystokinin, as a neuro modulator, became an important
anti-cancer target, especially when it was shown that cholecystokinin
regulates the invasiveness of human pancreatic cancer cell lines via the
protein kinase C pathway. The low potency and the lack of subtype
receptor selectivity of those early non-peptide CCK-antagonists, was
improved in the following generations of CCK antagonists. These potent
and selective antagonists have shown disappointing results in clinical
trials due to a poor bioavailability. Initially cholecystokinin was
discussed as growth factor, not only in pancreatic cancer, but also for
lung, breast, colon and brain cancer, followed by a detailed discussion
of over 20 different chemical classes having been developed to date,
mainly for the area of neuroscience. Loxiglumide, CI-988, Devazepide,
L-365,260 and YM022 are highlighted including in vivo studies and
clinical trials. Moreover, CCK antagonists were found useful in the
enhancement of the analgesic effects of morphine and the anti-neo
plastic effect of cis-platinium. Clinical trials are ongoing. It is
concluded that non peptidal cholecystokinin receptor antagonists are
modern, non-toxic anti-cancer agents.
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