Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors

ArticleinBioorganic & medicinal chemistry letters 22(15):5144-9 · August 2012with11 Reads
DOI: 10.1016/j.bmcl.2012.06.021 · Source: PubMed
Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC(50)) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC(50)) was low.
  • [Show abstract] [Hide abstract] ABSTRACT: The installation of geminal substitution at the C5' position of the carbosugar in our pyrimidine-derived hepatitis C inhibitor series is reported. SAR studies around the C5' position led to the installation of the dimethyl group as the optimal functionality. An improved route was subsequently designed to access these substitutions. Expanded SAR at the C2 amino position led to the utilization of C2 ethers. These compounds exhibited good potency, high selectivity, and excellent plasma exposure and bioavailability in rodent as well as in higher species.
    Article · Sep 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Three-dimensional quantitative structure activity relationship has been carried out on a series of 211 pyrimidine derivatives as HCV replication (replicase) inhibitors to identify the chemical structural impacting the biological activities. The QSAR models based on 157 compounds screened as the training set and the rest as the test set were established by comparative molecular field analysis and molecular similarity indices analysis (CoMSIA) methods. The optimal CoMSIA model exhibits both satisfying internal and external prediction performance with q 2 = 0.501, \( R^{ 2}_{\text{ncv}} \; = \; 0. 9 6 2 \) , \( R^{ 2}_{\text{pred}} \; = \; 0. 8 8 3 \) . In addition, the 3D contour map analysis and the pharmacophoric features identified from corresponding pharmacophore study point out the key structural features that affect the inhibition activity of the pyrimidine analogs that (1) bulky substituents at position 11 and 23 are unfavorable; (2) minor positive 16 charges and H-bond donor groups at this position are benefit while H-bond acceptor near this position are detrimental; (3) substituents near Ring B: minor H-bond donor, H-bond acceptor groups are favorable; (4) electro-negative charges at position 7 and 9 are favorable while H-bond donor at position 9 are unfavorable; (5) two H-bond donor sites (DS1, DS2), two H-bond donor atoms (DA1, DA2); two H-bond acceptor atoms (AA1, AA2), hydrophobic and aromatic, and aromatic centers account for the pharmacophore features of the model.
    Article · May 2015