During the CBCS screening campaign we identified the

During the CBCS screening campaign, we identified the series of bi-cyclic compounds summarised in . Isoxazolo[4,5-]pyridin-4(5)-one was the most common core in this class, but isoxazolo[4,5-]pyrimidin-4(5)-one and furo[3,2-]pyridin-4(5)-ones were present too. The phenyl ring was substituted at R3 with a nitrogen-containing group, such as dimethylamine (), succinimide (), pyrrolidine (), morpholine () or piperazine (), to give single-digit micromolar or sub-micromolar IC values. Larger substituents, such as 4-benzylpiperidinyl () or a benzyloxy group (), or removal of the R3 group, were not tolerable structural modifications ( and ). The R4 position was generally a methyl group, but it Obeticholic Acid could also accommodate a benzyl group (. ), and the R1 position accepted aromatic substituents, such as phenyl ( and ) or pyridyl ( and ). Isoxazolo[4,5-]pyrimidin-4(5)-one examples containing active structural motifs, such as aryl R1 and amine R3, also displayed inhibitory activity ( and ), with the chloro-phenyl derivative being the most potent inhibitor in this class (IC=0.28µM). A furo[3,2-]pyridin-4(5)-one core with an aryl ring at the R2 position instead of the R1, was completely inactive (. ), and highlighted the importance of this region of the scaffold. Despite the sub-par LE and LLE, when compared with other series (e), the aliphatic amine group present in this series, increased the Fsp3 (f), and could provide a handle to improve aqueous solubility during hit optimisation.
Introduction Deamination of cytidine nucleotides to uridine nucleotides is essential for conversion to thymidine nucleotides. However, uracil-containing intermediates can be mutagenic or cytotoxic. Deoxyuridine 5′-triphosphate nucleotidohydrolases (dUTPases) play an essential role in the nucleotide metabolism of all organisms by catalyzing the hydrolysis of dUTP to dUMP+pyrophosphate (Ppi).1., 2. This provides dUMP, a precursor for dTTP synthesis by thymidylate synthase, and protects DNA from misincorporation of dUTP in place of dTTP by lowering dUTP:dTTP ratios. Uridine nucleotides can also arise in DNA through the spontaneous deamination of cytidine, which accounts for a significant percentage of DNA base damage. If left unrepaired, uracil can create CG to TA transition mutations. When uracil is found in DNA, either from misincorporation instead of thymine or spontaneous deamination of cytosine, the base excision repair pathway is initiated by uracil DNA glycosylase (UDG), which recognizes a U:A mispair but which can result in apyrimidinic sites or DNA strand cleavage if the damage is not properly processed. To adjust levels of dCTP in relation to dTTP in the nucleotide pool, dCTP can be converted to dUTP in archaea and some bacteria by dCTP deaminase, then acted upon by dUTPase to form dUMP. dUMP is subsequently converted to dTTP by thymidylate synthase and thymidylate kinase. Eukaryotes and some bacteria create dUMP directly from dCMP via a zinc-dependent dCMP deaminase.6., 7.