International peer reviewd journal publications.
Medrxiv, a pre-print journal published by BMJ (British Medical Journal) and Yale University
Randomized, Comparative, Clinical Trial to Evaluate Efficacy and Safety of PNB001 in Moderate COVID-19 Patients |
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Medwin Publishers:
A Randomized, Comparative Clinical Trial to Evaluate Efficacy and Safety of PNB-001 as Immune Modulator in Moderate COVID-19 Patients |
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ResearchGate:
A Randomized, Comparative, Clinical trial to Evaluate Efficacy and Safety of PNB-001 as IMMUNE MODULATOR in Moderate COVID-19 patients |
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Novel, isoform-selective, cholecystokinin A receptor antagonist inhibits colon and pancreatic cancers in preclinical models through novel mechanism of action
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Irreversible Cholecystokinin-1 Receptor Antagonists PNB-028/81: N-isobutyl-5-hydroxy-5-aryl-pyrrol-2-ones as Experimental Therapeutic Agents against Colon and Pancreatic Cancer
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Cholecystokinin-2/gastrin antagonists: 5-hydroxy- 5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease
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Breaking into Merck’s CCK Patents: the Starting Point of PNB Vesper Life Science to Design and Develop Cholecystokinin(CCK)-Antagonists as Targeted Chemotherapeutics
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N‒substituted 5‒hydroxy‒pyrrol‒2‒ones based cholecystokinin‒2 antagonists as experimental anticancer agents for the treatment of lung cancer
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From Merck’s CCK- Antagonists Via 4-Amino-2(5H)- Furanones towards 5-Hydroxy-Pyrrol-2-Ones: Design, Synthesis and Evaluation of PNB-001 & PNB-081 as Experimental Therapeutic Agents in Pain Management
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CCK2 (one-2-Pyrrol-Dihydro-5, 1-Phenyl-5-Phenylethyl-1-Hydroxy-5Chloro-4 (001-PNB of Development: Antagonist Gastrin– as Analgesic Inflammatory-Anti
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Irreversible Cholecystokinin-1 Receptor Antagonists Pnb-028/81: N-Isobutyl-5-Hydroxy-5-Aryl-Pyrrol-2- Ones as Experimental Therapeutic Agents against Colon and Pancreatic Cancer
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Pre-Clinical Evaluation of CCK2 Antagonist PNB-001 (4-Chloro-5-Hydroxy- 1-Phenylethyl-5-Phenyl-1,5-Dihydro-Pyrrol-2-One) Towards The Design For A First-In-Man Clinical Trial
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CCK-Antagonist PNB-081 (Isobutyl-5-Hydroxy-5-Phenyl-Pyrrol- 2-One) as Adjunct to Opiates
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Cholecystokinin Antagonists: Fluorinated 5-Hydroxy-5- Aryl-Pyrrol-2-Ones as Experimental Agents for Brain, Colon and Pancreatic Cancer
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Analgesic Effects of 5-Alkyloxy-4-amino-2(5H)-furanones as Cholecystokinin-2 Antagonists
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Cholecystokinin-1 receptor antagonists: 5-hydroxy- 5-aryl-pyrrol-2-ones as anticancer agents†‡
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Abstract: Colon and pancreatic cancers contribute to 90,000 deaths each year in the USA. These cancers lack targeted therapeutics due to heterogeneity of the disease and multiple causative factors. One important factor that contributes to increased colon and pancreatic cancer risk is gastrin. Gastrin mediates its actions through two G-protein coupled receptors (GPCRs): cholecystokinin receptor A (CCK-A) and CCK-B/gastrin receptor. Previous studies have indicated that colon cancer predominantly expresses CCK-A and responds to CCK-A isoform antagonists. However, many CCK-A antagonists have failed in the clinic due to poor pharmacokinetic properties or lack of efficacy. In the present study, we synthesized a library of CCK-A isoform-selective antagonists and tested them in various colon and pancreatic cancer preclinical models. The lead CCK-A isoform, selective antagonist PNB-028, bound to CCK-A at 12 nM with a 60-fold selectivity towards CCK-A over CCK-B. Furthermore, it inhibited the proliferation of CCK-A-expressing colon and pancreatic cancer cells without affecting the proliferation of non-cancerous cells. PNB-028 was also extremely effective in inhibiting the growth of MAC-16 and LoVo colon cancer and MIA PaCa pancreatic cancer xenografts in immune-compromised mice. Genome-wide microarray and kinase-array studies indicate that PNB-028 inhibited oncogenic kinases and angiogenic factors to inhibit the growth of colon cancer xenografts. Safety pharmacology and toxicology studies have indicated that PNB-028 is extremely safe and has a wide safety margin. These studies suggest that targeting CCK-A selectively renders promise to treat colon and pancreatic cancers and that PNB-028 could become the next-generation treatment option.
Download Full versionAbstract:A new class of 5-arylated 5-hydroxypyrrolones was derived from mucochloric acid in 2 synthetic steps and the chemical structure was confirmed additionally by x-ray analysis. Using a radiolabelled binding assay, potent CCK1 selective ligands were identified (CCK1: 12nM) and the antagonism was confirmed by using isolated tissue preparations. A series of isobutyl derivatives displayed unsurmountable CCK antagonistic properties and in vitro excellent inhibition of proliferation was obtained in cholecystokinin related cancer cell lines in the nanomolar range. Finally, using xenograft studies in nude mice, two selected pyrrolone derivatives, X=H and X= F a fluorinated analogue ( PNB-028 ), showed a strong inhibition of tumour growth in a chemo-resistant colon cancer- (MAC 16) and a human pancreatic cell line (MIAPACA) at 50 mg/kg by oral administration.
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