Products

TGOFO2N
Therapeutic Area(s): Schizophrenia
Phase of Development: Phase II

Development Status:
Phase II

Product Description
TGOF02N is a 5HT2/D2 atypical antipsychotic. Like other atypical antipsychotics TGOF02N has the highest receptor binding for the dopamine D2 and D3 receptors, the serotonin 5HT2C and 5HT2A receptors, the adrenergic 1 receptor and the histamine H1 receptor, and is moderate affinity for the D1, D4 and 5HT1A receptors as well.

TGOF02N HCl exhibited dose-related antipsychotic activity in several animal behavioral models. TGOF02N HCl inhibited amphetamine-induced hyperactivity in mice over a dose range of 0.0625 to 0.5 mg/kg (ID50 value = 0.16 mg/kg). Its activity was similar to that of risperidone and haloperidol, and greater than that of clozapine. The ability of TGOF02N HCl (0.0625 to 0.5 mg/kg) to inhibit apomorphine-induced climbing behavior in mice and apomorphine-induced hyperactivity in mice suggested its potential beneficial effects on the positive symptoms of schizophrenia. Because of its alpha-adrenergic antagonist activity, TGOF02N HCl protected mice against noradrenaline-induced lethality (ED50=0.05 mg/kg); this suggested a potential to mitigate the positive symptoms and ameliorate the cognitive symptoms of schizophrenia; its potency in this test was similar to that of risperidone. TGOF02N HCl also inhibited MK-801-induced hyperactivity in mice (ID50=0.23 mg/kg), which suggested its potential beneficial effect on the negative symptoms of schizophrenia. TGOF02N HCl inhibited the 5HT2A receptor in the DOI-induced head twitch test in mice. This suggested that TGOF02N HCl might provide an amelioration of both positive and negative symptoms of schizophrenia with a low incidence of extrapyramidal symptoms. TGOF02N HCl also demonstrated 5HT2C receptor antagonism in the mCPP-induced hypolocomotion test in rats.

TGOF02N HCl did not protect mice against physostigmine-induced lethality at oral dosages of 4 or 8 mg/kg. This 8 mg dose was approximately 33 times the ID50 value for TGOF02N HCl with respect to the inhibition of apomorphine-induced climbing behavior (0.24 mg/kg), which is associated with antipsychotic activity. This suggested that TGOF02N HCl would have a low incidence of antimuscarinic side effects at effective antipsychotic doses. The ID50 value for TGOF02N HCl (18.40 mg/kg) with respect to apomorphine induced climbing assay in mice, suggests a potential lack of extrapyramidal side effects at antipsychotic doses. TGOF02N HCl showed an antagonistic effect on dopamine D1 receptors (ID50 = 0.31 mg/kg) in the SKF38393-induced grooming test in mice, which suggested a possibility of lesser extrapyramidal side effects.

Clinical Trials
Three Phase I trials have been conducted in normal healthy males. Two were single dose, dose escalation studies and the third was a multiple dose, dose escalation study.

The single dose studies showed that in the oral dose range 0.5 to 1.5 mg pharmacokinetics were linear with Tmax between 2 and 4 hours and 1/2 between 2 and 3 hours.

In the multiple dose study 0.5, 1.0, or 1.5mg was given daily for 7 days. TGOF02N was rapidly absorbed with Tmax of about 2.5 hours and 1/2 from 3.24 to 3.84 on both days 1 and 7. There was no accumulation.

In both studies, the most frequent adverse event was postural hypotension manifested by increased heart rate, decreased standing blood pressure, and in some cases dizziness.

Electrocardiographic examinations revealed no abnormalities including no changes in QTc.

Partners
Developmental and marketing partnerships are available.