When the same replacement was applied to the opioid antagonist, naltrexone 30a and its receptor agonist, oxymorphone 30b. the opiate sulfonamides (31a. 31b) were found to be devoid of agonist or antagonist activity (27). The lack of significant binding affinity of 31a and 31b may be attributed to the steric bulk of the sulfone moiety, which makes the sulfonamide group an unsuitable bioisosteric replacement for the phenolic hydroxy in this particular series.

Restriction of conformation is the most commonly used technique in SAR development (28). The conformational restrictions of a lead structure are often associated with decreased entropy and increased binding affinity and specificity with targets if the vectors of the binding elements are orientated toward the correct binding pockets of the targets. Additionally, by systematically reducing the rotatable bonds in the lead compounds, the resulting compound may have a better chance to have oral bioavailability. After analyzing 1100 compounds, it has been reported that the candidate compounds with fewer than 10 rotatable bonds had a higher instance of good oral bioavailability in rat (29).

Adenosine receptor agonists or antagonists play important roles in a variety of physiological functions in human. Recently, 32 was discovered as a novel non-xanthine adenosine Ai receptor antagonist. The oral bioavailability of 32 was relatively low due to a rapid first-pass effect in the liver and poor water solubility. Additionally, 32 was readily converted to the less active cis isomer in solution due to a facile photochemical trans-cis isomerization process. Compound 33 was designed using heteroaryl groups to mimic the double bond and carbonyl group of the acryloyl moiety (30). Compared with the original lead, compound 34 is more hydrophilic and soluble in water and has improved oral bioavailability. As a result, compound 34 was found to be 10 times more potent than 32 for in vivo diuretic activity despite a relatively low affinity for the adenosine A1 receptor.

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