Biopharmaceutical profiling of a pyrido[4,3-d] pyrimidine compound library.
The pyrido-pyrimidine structure is associated with different biological activities, including kinase inhibition and antibacterial activity. However, drug-like properties of this scaffold have not been explored thoroughly. Therefore, the biopharmaceutical profile of ten pyrido[4,3-d]pyrimidines with different substitution pattern was determined at the intestinal and hepatic level. The compounds' biopharmaceutical properties were significantly affected by the substitution pattern, resulting in a broad range in fasted state simulated intestinal fluid solubility values (1.9 μM-4.2 mM) and Caco-2 permeability coefficients (0.17×10(-6) cm/s to 52×10(-6) cm/s). A phenylhydrazido group was responsible for the low FaSSIF solubility. Caco-2 permeability was impaired by a dimethoxyphenyl substituent. All analogs were metabolically stable in human intestinal microsomes. The hepatic metabolism, reflected by the extraction ratio, was intermediate to high (ER>0.3). Aliphatic chains, methoxy groups on a phenyl substituent, ketone and amine substituents were predicted as most susceptible sites for hepatic metabolism. Correlations were found between polar surface area of the compound and Caco-2 permeability (R=0.86) and metabolic stability (R=0.76). No toxicity was seen for the pyrido[4,3-d]pyrimidines with Caco-2 cells and sandwich-cultured rat hepatocytes. In conclusion, the large diversity of substituents on the pyrido[4,3-d]pyrimidine core highly influenced the compounds' drug-like properties.
['Wuyts|Benjamin|B|', 'Keemink|Janneke|J|', 'De Jonghe|Steven|S|', 'Annaert|Pieter|P|', 'Augustijns|Patrick|P|']
D042931:Aldehyde Oxidase D000818:Animals D018938:Caco-2 Cells D002470:Cell Survival D002478:Cells, Cultured D003577:Cytochrome P-450 Enzyme System D022781:Hepatocytes D006801:Humans D007408:Intestinal Absorption D007413:Intestinal Mucosa D008861:Microsomes D011743:Pyrimidines D051381:Rats D054852:Small Molecule Libraries
Biopharmaceutical profiling Pyrido[4,3-d]pyrimidines Caco-2 Clearance prediction Sandwich cultured rat hepatocytes Suspended rat hepatocytes