Pyrrolidinebased inhibitors

Screening a library of a and p amino acids resulted in the discovery of 28 as a competitive inhibitor with a K value of 58 mM [59]. Replacement of the tert-but-oxycarbonyl group with various amides improved the potency significantly with the best compound in this series having a K value of 1 mM against the enzyme [66]. Further substitution at the 5 position with CH2NHCOR (where R is Me, Et, CH = CH2, i-Pr, CF3) did not increase binding affinity [66]. Replacement of the amino group at the 4-position by alkylamino, amides, and guanidine also did not result in compounds with better inhibitory activity [66]. A different substitution on the pyrrolidine core resulted in 29 when R = ester and amine and R' = CH2CH(CH3 or C2H5)2. These changes improved the potency in this series, with the best compound being R = CO2CH3 and R' = CH2CH(C2H5)2, and having a K value of 0.8 nM [65]. Additional modifications of the R group were investigated fixing R' as CH2CH(CH3)2 as shown in 30 [67]. Compounds with various R groups including esters, ethers, ketones, amides, heterocyclics, and substituted vinyls were prepared. SAR identified cis-propene to be the optimum group. Compounds with this substituent showed K values of 0.02-0.8 mM [67]. Final optimization of the alkyl side chain resulted in the most active compound (31) in the series, with a K value of 0.2nM. The detailed synthesis of 31 was reported [68-70]. Pyrrolidine compounds are well covered in a recent review article [71].

CO2H

CO2H

CO2H

CO2H

CO2H

CO2H

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