Authors
Benjamin Wuyts, Janneke Keemink, Steven De Jonghe, Pieter Annaert, Patrick Augustijns
Published in
International journal of pharmaceutics. Volume 455. Issue 1-2. Pages 19-30. Oct 14, 2013. Epub Aug 06, 2013.
Abstract
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.
PMID:
23933051
Bibliographic data and abstract were imported from PubMed on 03 Feb 2014.
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