Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase - PubMed (original) (raw)

Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase

Dustin D Hawker et al. Bioorg Med Chem. 2012.

Abstract

Two principal neurotransmitters are involved in the regulation of mammalian neuronal activity, namely, γ-aminobutyric acid (GABA), an inhibitory neurotransmitter, and L-glutamic acid, an excitatory neurotransmitter. Low GABA levels in the brain have been implicated in epilepsy and several other neurological diseases. Because of GABA's poor ability to cross the blood-brain barrier (BBB), a successful strategy to raise brain GABA concentrations is the use of a compound that does cross the BBB and inhibits or inactivates GABA aminotransferase (GABA-AT), the enzyme responsible for GABA catabolism. Vigabatrin, a mechanism-based inactivator of GABA-AT, is currently a successful therapeutic for epilepsy, but has harmful side effects, leaving a need for improved GABA-AT inactivators. Here, we report the synthesis and evaluation of a series of heteroaromatic GABA analogues as substrates of GABA-AT, which will be used as the basis for the design of novel enzyme inactivators.

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Figures

Figure 1

Previously described GABA-AT inactivators (1 and 2), aromatic substrates (3), and the new series of heteroaromatic analogues (4–6).

Scheme 1

Catalytic mechanism for GABA-AT.

Scheme 2

Mechanisms of inactivation of GABA-AT by vigabatrin (1). Pyr stands for the pyridoxal 5′-phosphate ring system.

Scheme 3

Synthesis of the 2,4-disubstituted furan and thiophene amino acids. Reagents and conditions: (a) i) Zn (s), NH4OH, H2O, ii) H2SO4, MeOH, reflux; b) Pd(PPh3)4, Zn(CN)2, DMF; c) Boc2O, NaBH4, NiCl2·6H2O (cat.), MeOH; d) LiOH·H2O, MeOH, H2O; e) 6 N HCl (aq.); f) NBS, benzoyl peroxide, CCl4; g) i) NaN3, DMF, ii) Boc2O, H2 (g), Pd-C, EtOAc.

Scheme 4

Synthesis of 3,4-disubstituted furan and thiophene amino acids. Reagents and conditions: a) 1 eq. NaOH, MeOH; b) BH3·THF, THF; c) PPh3, CCl4, CH2Cl2; d) i)NaN3, DMF, ii) Boc2O, H2 (g), Pd-C (cat.), EtOAc; e) LiOH· H2O, MeOH, H2O; f) 6 N HCl (aq); g) H2SO4, MeOH; h) PPh3, CBr4, CH2Cl2.

Scheme 5

Synthesis of 2,4- and 2,5-disubstituted pyrrole amino acids. Reagents and conditions: a) POCl3, DMF, CH2Cl2; b) NH2OH·HCl, K2CO3, H2O; c) Boc2O, H2 (g), Pd-C (cat.), EtOAc; d) LiOH·H2O, MeOH, H2O; e) 6 N HCl (aq).

Scheme 6

Synthesis of deuterated 5a. Reagents and conditions: a) Boc2O, NaBD4, NiCl2·6H2O (cat.), MeOH; b) LiOH·H2O, MeOH, H2O; c) 6 N HCl (aq.).

Scheme 7

Presumed substrate mechanism of 5a or [_D_2]-5a.

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Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase - PubMed (original) (raw)