Tiagabine development

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. 

Sudden unexpected death in epilepsy (SUDEP) There have been as many as 10 cases of SUDEP during the clinical development of tiagabine among 2531 patients with epilepsy (3831 patient-years of exposure). 

Serious rash Four patients treated with tiagabine during premarketing clinical testing developed what were considered to be serious rashes. In 2 patients, the rash was described as maculopapular in 1 it was described as vesiculobullous and in the fourth case, a diagnosis of Stevens-Johnson syndrome was made. Drug associated rash can, if extensive and serious, cause irreversible morbidity, even death. 

Of the newer anticonvulsants, lamotrigine, gabapentin, tiagabine, and vigabatrin have little or no teratogenic potential in animals, whereas oxcarbazepine and topira-mate are teratogenic in rodents. However, animal studies are not necessarily apphcable to humans and chnical data are stiU insufficient to assess the effects of newer drugs on the development of the human fetus (153). 

After an increase in tiagabine dose to 32 mg/day, a 28-year-old woman with partial epilepsy developed a prolonged and disoriented state associated with generalized spike-and-wave discharges on the electroencephalogram. Tiagabine was withdrawn and the status did not recur. 

A 42-year-old woman developed thrombocytopenia (platelet count 4 x 10 /1), ecchymoses, and petechiae after taking tiagabine 50 mg/day for about 1 month (26). Bone-marrow biopsy showed a moderate increase in megakaryocytes without signs of disturbed maturation. Withdrawal of tiagabine led to gradual recovery. 

Tiagabine, (14) 1990 Developed by Novo Nordisk A/S, Denmark Synthesized by Braestrup et al. ... 

A review of the second-generation anticonvulsants reveals that screening or serendipity led to the development of felbamate (10), 1am-otrigine (11), zonisamide (13), topiramate (15), and levetiracetam (16) on the other hand, clobazam (4d) and oxcarbazepine (12) were developed by structural variation of known agents (78). Only three, vigabatrin (8), gabapentin (9), and tiagabine (14), were developed by mechanism-based rational development (78). 

Further developments demonstrated that the 4,4-diphe-nyl-3-butenyl moiety could be replaced by ether-type analogues and that the attachment of a lipophilic 3,3-diphenylpropyl side chain can take place at the carbon atom at the 6-position of the amino acid. However, in this latter case, despite a reasonable in vitro activity (IC50 =100 nM), no in vivo activity is observed. Final optimization of SKF 89976A led to the iis-thiophene tiagabine. ... 

Side effects are more common with tiagabine than with other adjunct drugs and most often involve the CNS. They include somnolence, headache, dizziness, tremor, abnormal thinking, depression, and psychosis. Furthermore, recent reports have implicated tiagabine in the development of nonconvulsive status epilepticus (88,89). There is an increased risk of seizure in patients being treated for off-label psychiatric indications. Tiagabine may interfere with visual color perception (90). 

Acid-catalyzed hydrolysis with aqueous hydrochloric acid was a facile process the hydrochloride salt of the product could be crystallized out of the same solution. 0.15 N hydrochloric acid was found to be optimally effective in cleaving the ester without ra-cemizing the chiral center. The methods developed here were general ones that could be adapted to the synthesis of several analogs of tiagabine. 

---