text: The common structure for analogs that inhibit TNF-α via inhibition of PDE4 is prepared on the basis of hydrolysing the glutarimide ring of thalidomide. These analogs do not have an acidic chiral hydrogen, unlike thalidomide, and would therefore be expected to be chirally stable.
  On the phenyl ring, a 3,4-dialkoxyphenyl moiety (Figure 6) is a known pharmacophore in PDE4 inhibitors such as rolipram. Optimal activity is achieved with a methoxy group at the 4-position (X2) and a bigger group, such as cyclopentoxy at the 3-position carbon (X3). However the thalidomide PDE4 inhibitory analogs do not follow the SAR of rolipram analogs directly. For thalidomide analogs, an ethoxy group at X3 and a methoxy group at X2, with X1 being just a hydrogen, gave the highest PDE4 and TNF-α inhibition. Substitutes larger than diethoxy at the X2–X3 position had decreased activity. The effects of these substitutions seem to be mediated by steric effects.
  For the Y-position, a number of groups have been explored. Substituted amides that were larger than methylamide (CONHCH) decrease PDE4 inhibition activity. Using a carboxylic acid as a starting point, an amide group has similar PDE4 inhibition activity but both groups were shown to be a considerably less potent than a methyl ester group, which had about six-fold increase in PDE4 inhibitory activity. Sulfone group had similar PDE4 inhibition as the methyl ester group. The best PDE4 inhibition was observed when a nitrile group was attached, which has 32 times more PDE4 inhibitory activity than the carboxyl acid. Substituents at Y leading to increasing PDE4 inhibitory activity thus followed the order:
  : COOH ≤ CONH ≤ COOCH ≤ SOCH < CN
  Substitutions on the phthaloyl ring have been explored and it was noticed that nitro groups at the C4 or C5 location decreased activity but C4 or C5 amino substitution increased it dramatically. When the substitution at the 4 (Z) location on the phthaloyl ring was examined, hydroxyl and methoxy groups seem to make the analog a less potent PDE4 inhibitor. An increase in activity was observed with amino and dimethylamino to a similar extent but a methyl group improved the activity further than the aforementioned groups. A 4-N-acetylamino group had slightly lower PDE4 inhibitory activity, compared with the methyl group, but increased the compound's TNF-α inhibitory activity to a further extent. Substituents at Z leading to increasing PDE4 inhibitory activity thus followed the order:
  : N(CH) ≤ NH