Pharmacophoreguided Optimization Of Compound 314

Examining the fit of compound 3.14 to the pharmacophore model in Figure 3.8, three observations of relevance for optimization of the compound with respect to affinity can be made.

• There is sufficient space at the position of the CF3 group to replace this group by a larger substituent.

• The ester ethyl group in 3.14 does not completely fill out the cavity in comparison to the bromo substituent in compound 3.2 (compare the fit of the bromo substituent in template molecule 3.12 in Figure 3.6). As this part of the shape is most probably a highly hydrophobic/lipophilic pocket, it is essential for optimal affinity to fill it out as completely as possible. Replacement of the ester ethyl group by a propyl group is an obvious possibility.

• Compound 3.14 has two conformations with respect to rotation around the bond connecting the ester group to the bicyclic ring system (Figure 3.10). A replacement of the ester group by an amide group would stabilize the molecule in the bioactive conformation due to the intermolecular hydrogen bond in the amide compound. This will give a smaller conformational entropy loss for binding and a higher affinity (for more details of entropy effects in ligand binding see Chapter 1).

On the basis of these observations, a small series of compounds were synthesized and tested. The most important compounds and their affinities are shown in Figure 3.11.

Bioactive conformation

3.14

3.16

3.17

3.18

3.14

3.16

3.17

3.18

3.17

3.19

3.20

FIGURE 3.11 Pharmacophore-guided optimization of compound 3.14.

3.17

3.19

3.20

FIGURE 3.11 Pharmacophore-guided optimization of compound 3.14.

The replacement of the CF3 group in 3.14 by an ethyl group to give 3.16 increases the affinity from 122 to 20 nM. Replacement of the ester ethyl group in 3.16 by a propyl group to give 3.17 further increases the affinity to 1.4 nM and conversion of the ester group in 3.17 to an amide group gives compound 3.18 with an affinity of 0.26 nM.

By further exploring lipophilic substituents in the 3'-position, compound 3.19 was identified to be a high affinity compound (Ki = 0.17 nM). Finally, converting the ester group in 3.19 to an amide group gave the highest affinity compound 3.20 in this series of compounds with Ki = 0.048 nM. In comparison with compound 3.14, compound 3.20 has a higher affinity by a factor of 2500. This increased affinity demonstrates the power of a well-developed pharmacophore model for the optimization of a compound with respect to affinity.

Was this article helpful?

0 0

Post a comment