Nonspecific covalent binding (bioactivation) may cause toxicological events. On the other hand, there are where controlled, target-specific covalent modification has proven useful. In ideal cases, the covalent modifier is typically poorly reactive with solution nucleophiles under physiological conditions, but yet upon appropriate positioning will selectively react with a nucleophile within the target protein. This review shows examples in which therapeutic targets are covalently bound by small molecule drugs. Orlistat, anti-obesity drug, has acylation mechanism with triacylglycerol lipase. Donepezil and galantamine are competitive binding with the active site serine of acetylcholinesterase. Aspirin irreversibly acylates an active site serine of prostaglandin endoperoxidase synthase. Omeprazole and ransoprazole, PPI, form disulfide bond formation. HKI-272 is an irreversible dual EGFR / HER-2 inhibitor by Michal addition. For recent noteworthy examples of Pinner reaction, cyanopyrrolidine of LAF-237 (DPP-IV inhibitor) forms a reversible covalent imidate ester adduct with the active site serine; dipeptidic nitrile of MK-0822 (Cathepsin K inhibitor) forms a reversible covalent thioimidate with the active site cysteine.
The starting compound 6 had low solubility due to high crystalline form and was a potent CYP2D6 inhibitor. (0.3 micro M). CYP2D6 inhibition significantly depended on Ar1's substitution. Especially replacement of CN with OH abolished CYP2D6 inhibition, therefore CN group of compound 6 probably interacted with the CYP2D6 enzyeme possibly through hydrogen bonding. Based on crystal structure of HCV polymerase, designed ethylphenyl analogue as 16 showed good potency. Replacement of ethylphenyl with ethylpyridiyl improved water solubility, metabolic stability, and potency. Finally, Pfizer's chemists discovered PF-00868554 with an excellent profile.
Compound 29, potent SIRT activator, has demonstrated oral antidiabetic activity in the ob/ob mouse, DIO mouse, and Zucker fa/fa rat model. This compound should be useful as chemical tool compound.