YM 992YM 35992

Adis Comments YM 992 (YM 35992) is a potential antidepressant agent undergoing phase IIclinical trials with Yamanouchi in Europe and the US, and undergoing preclinicalinvestigation in Japan. It appears to act as a selective serotonin (5-hydroxytrypt-amine; 5-HT) uptake inhibitor and serotonin 5-HT2A receptor antagonist.YM 992 is a novel compound with both serotonin reuptake inhibitory and

5-HT2A receptor antagonist activity, offering an alternative to tricyclic antide-pressants and selective serotonin reuptake inhibitors. Selectivity for these sys-tems is relatively high.

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Table I. Features and properties

Chemical name (−)-(S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochlorideMolecular formula C14 H18 F N O2 . HClCAS number N06A (Antidepressants)WHO ATC code N6A (Antidepressants)Originator Companies Yamanouchi, JapanHighest development phase Phase II (Europe and USA)

PropertiesMechanism of action Serotonin 5-HT2A receptor antagonists; serotonin uptake inhibitorsPharmacodynamics Antidepressant activity in animal modelsRoute of administration POAdis rating 64

Profile

Adverse Events

The intrinsic α1-adrenoceptor antagonistic ac-tivity of YM992 in pithed rats was 10 times weakerthan that of trazodone. In addition,YM922 lacked ananticholinergic effect in mice. These results indicatethat, like selective serotonin (5-hydroxytrptamine;5-HT) reuptake inhibitors, YM 922 may have an

improved safety profile compared with tricyclicantidepressants,[1]

Pharmacodynamics

In the rat frontal cortex, YM 992 dose-depend-ently increased extracellular serotonin levels. 14days’ treatment (30 mg/kg IP twice daily) signifi-cantly increased [3H]8-OH-DPAT binding sites.[2]YM 992 was highly active in the mouse tail

suspension test; it decreased immobility time in adose-dependent manner with a statistically signif-icant effect at 34.2 mg/kg PO. Single dose and longterm treatment with YM 992 11.4 mg/kg IP amel-iorated the learning deficit in olfactory-bulbectom-ised rats when performing a passive avoidancetask.[1]

References1. Takeuchi H, Yatsugi S-i, Hatanaka K-I, et al. Pharmacological

studies on YM992, a novel antidepressant with selective se-rotonin re-uptake inhibitory and 5-HT2A receptor antagonis-tic activity. Eur J Pharmacol 1997 Jun; 329: 27-35

2. Hatanaka K, Nomura T, Yatsugi S, et al. Biochemical studies ofYM992: a novel putative antidepressant. Jpn J Pharmacol1996; 71 Suppl. I: 280

Table II. Drug development history

Sep 1998 Phase II clinical trials for depression in Europe (PO)Sep 1998 Phase II clinical trials for depression in USA (PO)Sep 1998 Preclinical development for depression in Japan

(PO)Feb 1998 Phase I clinical trials for depression in European

Union (PO)Feb 1998 Phase I clinical trials for depression in USA (PO)Oct 1997 Phase I clinical trials for depression in Japan (PO)Feb 1997 Preclinical development for depression in Japan

(unknown route)

YM 992 71

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