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The simple 2-pyridine carboxamide 21 showed low nanomolar activity on the enzyme, a 6-fold shift in
the spread assay in low serum, but reduced activity in high serum (IC50 = 0.02
?M; CIC95 = 0.125 ?M 10% FBS; CIC95 = 1.00 ?M 50% NHS). The other pyridine
isomers were less potent in the cell based assay (data not shown). The
introduction of a second nitrogen in the ring led to the more polar pyridazine
derivative which showed a reduced shift in potency between the low and high
serum conditions (CIC95 = 0.062 ?M 10% FBS; CIC95 =0.50 ?M 50% NHS). The
isomeric pyrimidine derivative 23
was potent in all assays (IC50 = 0.007 ?M; CIC95= 0.02 ?M 10% FBS; CIC95 =
0.050 ?M 50% NHS). Five-membered ring heterocycles were also investigated in
depth, and compounds bearing two or three heteroatoms were the most potent in
the cell based assays, with heterocycles having a heteroatom in the 2-position
being the most active. Oxazole 24,
thiazole 25, and imidazole 26 all showed single-digit nanomolar
activity on the enzyme. In contrast, in the cellular antiviral assay, they
showed different degrees of activity. Oxazole 24 had CIC95 = 0.50 ?M in both
serum conditions, while thiazole 25
had higher activity in low serum and showed 4-fold shift in high serum and
imidazole 26 showed the best activity in high serum conditions (CIC95 =0.250 ?M
50% NHS). Among the heterocycles having three heteroatoms, oxadiazole 27 was the best, being one of the most
potent compounds in the cell based assay (CIC95= 0.019 and 0.031 ?M in 10% FBS
and 50% NHS, respectively). Other heterocycles having a similar heteroatom
arrangement, including the corresponding triazole 28, showed a lower activity in the antiviral assay. Thus, compound 27 showed most potent among all the
compounds of this series.

Both
compounds 27 and 11 exhibit equal and promising
pharmacokinetic properties. Taking into account the intrinsic potency in the
cell based assay in high serum condition and the mutant profile, compound 27
was selected over 11. The
compound 27 was MK-0518 of Merck, which entered clinical trials and
approved by FDA in 2007 as first integrase inhibitor. 17

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