The Discovery and Structure Activity Relationship of Pregabalin A Second Fortuitous Discovery

Much like gabapentin, pregabalin was identified through a somewhat circuitous path. R. Silverman (Northwestern University) developed a series of 3-alkyl-4-aminobutyric acids as part of a program to develop activators of glutamic acid decarboxylase (GAD), a pyridoxyl 5'-phosphate-dependent enzyme involved in the synthesis of GABA in the brain.20'21 In this work, racemic 3-isobutyl-g-aminobutyric acid was found to be a weak activator of GAD but the most potent compound in the prevention of tonic extensor seizure in mice.22,23 Yuen went on to synthesize both enantiomers of 3-isobutyl-g-aminobutyric acid using an oxazolidinone approach,24 and further studies showed that (S)-isobutyl-g-aminobutyric acid (also known as PD 0144723, CI-1008, pregabalin, Lyrica) dose-dependently inhibited the binding of [3H]-gabapentin to pig brain membrane whereas the corresponding R-isomer had 12-fold less affinity for binding and no activity in a seizure model in vivo.25 This report supported other findings suggesting that binding affinity at a2-S was a critical component of the pharmacology of this class of compounds.

One of the first large reports of the SAR of pregabalin was published by Belliotti et al. ( ). This study examined the effects of modifying the pregabalin backbone at the 2-, 3-, and 4-positions of the butyric acid backbone and the 1-position of the isobutyl side chain. These studies looked more comprehensively at preclinical activities in animal models of seizure, analgesia, and anxiety as well as activity at the LAT-1 amino acid transporter. For the first time, preliminary observations on the divergence in SAR between affinity for the a2-S protein and affinity for system L transport were reported.

Much like the SAR seen to date with compounds related to gabapentin, subtle changes in the arrangement of the carbon skeleton drastically altered the affinity of pregabalin for the a2-S subunit. For instance, in the SAR seen in 2- and 3-analogs of pregabalin, transposition of the side chain to the 2-position (43) greatly reduced binding affinity. Similarly, incorporation of the methyl moiety at the 2-position (44) and 3-position (45) reduced binding considerably. It is also interesting to note the tolerance to structural changes shown by the system L transporter. Rearrangement of the alkyl side chain did not greatly shift the affinity of compounds for system L transport; the only major structural

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