Nipecotic acids

Enantiopure (R)- and (S)-nipecotic acid (Nip) derivatives 64 were obtained following classical resolution of ethyl nipecotate with either enantiomer of tartaric acid and successive recrystallization of the corresponding salts [153, 154, 156] or by resolution of racemic nipecotic acid with enantiomerically pure camphorsul-fonic acid [154]. N-Boc protected pyrrolidine-3-carboxylic acid (PCA) 65 for the synthesis of homo-ohgomers [155] was prepared by GeUman from trans-4-hydroxy-L-prohne according to a known procedure [157]. 

As a result of their capacity to tolerate very different kinds of y9-peptidic turns (120 versus 122) and different stereochemistries in the turn segment (compare S/ R and R/S nipecotic acid dipeptide sequences), hairpin stmctures formed by fS-peptides reveal unusually high plasticity compared to a-peptide y9-hairpins. 

In parallel with the identification of distinct transporters for GABA there has been continued interest in the development of selective blockers of these transporters and the therapeutic potential that could result from prolonging the action of synaptically released GABA. It has been known for a long time that certain pro-drugs of nipecotic add (e.g. nipecotic acid ethyl ester) are able to cross the blood-brain barrier and are effective anticonvulsants in experimental models of epilepsy. More recently, several different systemically active lipophillic compounds have been described that act selectively on GAT-1, GAT-2 or GAT-3 (Fig. 11.4). Of these, tiagabine (gabitiil), a derivative of nipecotic acid that acts preferentially on GAT -1, has proved clinically useful in cases of refractory epilepsy. 

Compound 1 was the first cyclopentane-based NK-1 receptor antagonist development candidate at Merck. It contains five stereocenters a central core possessing three contiguous all-trans stereocenters, a pendent bis(trifluoromethyl)-benzyHc ether, and a nipecotic acid moiety (Figure 7.1). Key to the successful preparation of 1 was construction of the trans, trans-cyclopentyl core and installation of the unsymmetrical secondary-secondary (sec-sec) ether. The preparation of 1 is the focus of this chapter. 

Novel sets of lipophilic molecules that do not contain the nipecotic acid moiety, have been shown to have higher affinity for GAT2 and GAT4 than for GATl and GAT3... 

During the last two decades, a large number of GABA analogs based on A-substitutions of the GABA mimetics nipecotic acid, guvacine, THPO, THAO, and exo-THPO... 

Krogsgaard-Larsen, P. and Johnston, G. A. R. (1975) Inhibition of GABA uptake in rat brain slices by nipecotic acid, various isoxazoles and related compounds. J. Neurochem. 25, 797-802. 

Larsson, O. M., Krogsgaard-Larsen, R, and Schousboe, A. (1980) High-affinity uptake of (RS)-nipecotic acid in astrocytes cultured from mouse brain. Comparison with GABA transport. J. Neurochem. 34, 970-977. 

Juhasz, G., Kekesi, K. A., Nyitrai, G., Dobolyi, A., Krogsgaard-Larsen, P., and Schousboe, A. (1997) Differential effects of nipecotic acid, and 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol on extracellular gamma-aminobutyrate levels in rat thalamus. Eur. J. Pharmacol. 331,139-144. 

Knutsen, L. J., Andersen, K. E., Lau, J., et al. (1999) Synthesis of novel GABA uptake inhibitors. 3. Diaryloxime and diarylvinyl ether derivatives of nipecotic acid and guvacine as anticonvulsant agents. J. Med. Chem. 42, 3447-3462. 

Andersen, K. E Lau, J., Lundt, B. F Petersen, H Huusfeldt, P. 0., Suzdak, P. D., and Swedberg, M. D. (2001) Synthesis of novel GABA uptake inhibitors. Part 6 preparation and evaluation of N-Omega asymmetrically substituted nipecotic acid derivatives. Bioorg. Med. Chem. 9,2773-2785. 

A few of the phenyl esters of nipecotic acid were also examined for their anticonvulsant effects and found to be active. The most stable ester was also the most active, but more labile esters were also effective. Because nipecotic acid itself was not used for comparison, no conclusion can be derived regarding the pharmacological value of such prodrugs. 

C. Altomare, A. Carotti, S. Cellamare, M. Ferappi, R. Cagiano, G. Renna, QSAR Analysis of Chemical and Serum-Catalyzed Hydrolysis of Phenyl Ester Prodrugs of Nipecotic Acid , Int. J. Pharm. 1988, 48, 91 -102. 

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