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.
Drug Delivery and Disposition, KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, Box 921, 3000 Leuven, Belgium.
Benjamin
B
Wuyts
Janneke
J
Keemink
Steven
S
De Jonghe
Pieter
P
Annaert
Patrick
P
Augustijns
D042931:Aldehyde Oxidase / Q000378:metabolism; D000818:Animals; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D054852:Small Molecule Libraries
D011743:Pyrimidines; D054852:Small Molecule Libraries; D003577:Cytochrome P-450 Enzyme System; D042931:Aldehyde Oxidase
Biopharmaceutical profiling; Caco-2; Clearance prediction; Pyrido[4,3-d]pyrimidines; Sandwich cultured rat hepatocytes; Suspended rat hepatocytes