Invited Speaker

Gabitril™ - a Drug for the Treatment of Partial Seizures Acting via Inhibition of GABA Uptake
Lars J.S. Knutsen
USA

Tiagabine is an example of a drug targeting a single mechanism of action, namely inhibition of the uptake of g-aminobutyric acid (GABA) - the major inhibitory neurotransmitter in the human brain. There are 4 discrete GABA transporters in the human Central Nervous System (CNS), hGAT1, hGAT2 and hGAT3, and the betaine transporter (hBGT1).¹ Gabitril emerged as a novel a nticonvulsant from a research program at Novo Nordisk in Denmark in the late 1980s, and was approved by the FDA in 1997 for the treatment of seizures, indicated as adjunctive therapy in adults and children 12 years and older in the treatment of partial seizures. Novo Nordisk developed the drug in collaboration with Abbott, who retained the North American market and licensed it for European co-marketing with Sanofi-Synthelabo. In November 2000, worldwide rights to Gabitril were transferred to Cephalon. There has been a clinical trial of Gabirtil in the treatment of Generalized Anxiety Disorder (GAD) and some publications of analgesic effects. It has not yet been approved for monotherapy or various other potential indications such as neuropathic pain, anxiety or sleep.




In the CNS, GABA acts at GABA_A receptors, which are ligand-gated ion channels, selectively permeable to chloride ions, and at GABA_B receptors are GPCRs, which decrease cAMP, open K+ channels. The initial stage of the design of the drug was by attachment of lipophilic anchors to the natural products, the cyclic amino acids nipecotic acid and guvacine.² The structures of Tiagabine, the lipophilic GABA-Uptake inhibitor CI-966 (Warner-Lambert) and the back-up compound NNC 05-0711³ are shown above, along with Gabapentin, a GABA analogue, which is a marketed drug but does not act via GABA-uptake inhibition.

The design of Gabitril and its back-up compounds such as NNC 05-0711, from the oxime series and alternate back-up compounds will be presented. The lecture will conclude with lessons and conclusions for drug development in the 21^st century.

1. Clark, J.E. & Clark, W.A. Handbook Exp. Pharm., 2001, 150, 355-372.
2. Andersen, K.E., Braestrup, C., Grønwald, F.C., Jørgensen, A.S., Nielsen, E.B., Sonnewald, U. Sørensen P.O., Suzdak, P.D. and Knutsen, L.J.S.; The Synthesis of Novel GABA uptake inhibitors. 1. Elucidation of the structure activity studies leading to the choice of R 1 [4,4 bis (3 methyl 2 thienyl) 3 but¬enyl] 3 piper¬idine carboxylic acid (Tiagabine) as an anticonvulsant drug candidate; J. Med. Chem., 1993, 36, 1716 1725.
3. Knutsen, L.J.S., Andersen, K.E., Lau, J., Lundt, B.F., Henry, R.F., Morton, H.E., Nærum, L., Petersen, H., Stephensen, H., Suzdak, P.D., Swedberg, M.D.B., Thomsen, C. and Sørensen P.O. The Synthesis of Novel GABA Uptake Inhibitors. 3. Diaryloxime and Diarylvinylether Derivatives of Nipecotic acid and Guvacine as Anticonvulsant Agents. J. Med. Chem., 1999, 42, 3447 - 3462.