Bioisosteric Replacements in Drug Design - New Developments in Medicinal Chemistry - page 222

Figure 4: Structure and IC 50 values for compounds with N -piperidylamide substituents. The IC 50
are presented for the CB1 antagonists with in vitro potency below 10nM.
Another interesting example is the application of the scaffold hopping approach in
the discovery of a novel indole series of EP 1 receptor antagonist as potential
analgesics [33]. The authors proposed the design of novel EP 1 receptor
antagonists for the treatment of inflammatory pain based on the concept that the
new template would have an improvement in potency, selectivity and/or
pharmacokinetics over the starting template. Stimulated by their previous reported
results regarding the pyrazole, thiazole and pyridine derivatives and intrigued by
the potential hydrogen bond formed between the ortho -alkoxy group and the
biaryl NH of a generic structure (Fig. 5A ), they synthesized a series of indole
compounds of general structure B (Fig. 5B ).
Figure 5: ( A ) Potential intramolecular bond that could be formed between the ortho-alkoxy group,
and ( B ) the biaryl NH of a generic structure.