Breaking into Merck’s CCK Patents: the Starting Point of PNB Vesper Life Science to Design and Develop Cholecystokinin(CCK)-Antagonists as Targeted Chemotherapeutics

Volume 1 - Issue 2

Eric Lattmann*¹ and Pornthip Lattmann²

Received: March 23, 2018;   Published: March 29, 2018

DOI: 10.32474/DDIPIJ.2018.01.000106

Full Text PDF

To view the Full Article   Peer-reviewed Article PDF

Abstract

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.

Abbrevations: GI: Gastrointestinal: Bt2cGMP:Dibutyryl Cyclic Guanosine Mono Phosphate; Bt2cGMP:Dibutyryl Cyclic Guanosine Mono Phosphate; CCK: Cholecystokinin

Abstract| Introduction| Cholecystokinin and Cancers| From CNS Drugs to New Anticancer Agents| Amino Acid Derivatives| Loxiglumide and Proglumide as Early Anti-Cancer Agents| Evaluation of CI-988 as Anti-Cancer Agent| Benzodiazepine Derivatives| Ureidobenzodiazepine Derivatives| Recent Clinical Studies| Potentiation of Clinical Effects| Conclusion| References|