YM 900YM 90K

Adis Comments YM 900 (YM 90K) is a selective and potent AMPA-type glutamate receptorantagonist. YM 900 is currently undergoing phase II studies for the treatment ofstroke with Yamanouchi in Japan. YM 900 also has potential for the treatment ofAlzheimer’s disease, as shown in preclinical testing, and appears to be undergoingphase I trials for the treatment of seizures. YM 900 is in preclinical developmentwith Zeneca in the USA as a potential antiparkinsonian agent.

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N N

NH

NH

ONO2

O

Table I. Features and properties

Chemical name 6-(1-Imidazolyl)-7-nitroquinoxaline-2,3-(1H,4H)-dione

Molecular formula C11 H7 N5 O4

CAS number 143151-35-3

WHO ATC code N03A-X (Other antiepileptics); N04 (Anti-Parkinson Drugs); N07A (Parasympathomimetics); N07X(Other Nervous System Drugs)

EphMRA ATC code N3A (Anti-Epileptics); N4A (Anti-Parkinson Drugs); N7 (Other CNS Drugs Including AntismokingProducts); N7D9 (All other anti-Alzheimer products)

Originator Companies Yamanouchi (Japan)

Highest development phase Phase II (Japan)

Properties

Mechanism of action AMPA receptor antagonists, Glutamate antagonists

Pharmacodynamics Neuroprotective, anticonvulsant and antiparkinsonian activity

Pharmacokinetics t1⁄2β 0.61-0.84h in adults; Vd 0.29-0.42 L/kg in adults; CL 33.54-37.8 L/h in adults

Route of elimination Renal

Route of administration Injection

Profile

Pharmacokinetics

The pharmacokinetics of YM 900 have been in-vestigated after single doses of 0.75 to 36mg andrepeated doses of 24mg bid given as 3h IV infu-sions in male volunteers. Unchanged plasma drugconcentrations reached a near steady state by theend of the 3h infusion and decreased rapidly in a

biphasic manner. After single doses, C3 andAUC∞ in a near dose-dependent manner. t1⁄2β (36.7to 50.4 min), CL (559 to 716 ml/min) and Vss (20.1to 29.7L) remained almost constant regardless ofdose or the individual. C3 values were similar aftereach repeated dose, suggesting no accumulation ofthe drug. Unchanged drug was rapidly excreted inurine by ≥90% of the dose within 1h of completionof infusion. There were no dose-dependent or indi-vidual differences in excretion.[1]

Adverse Events

YM 900 was well tolerated after single doses of0.75 to 36mg and repeated doses of 24mg bid for3 days given as 3h IV infusions in male volunteers.One volunteer participating in the single dose stud-ies complained of sleepiness. YM 900 did not af-fect insulin secretion from the pancreas. No signif-icant abnormalities attributable to YM 900 wereobserved in objective or subjective symptoms, vi-tal signs or routine laboratory tests.[1]

Pharmacodynamics

YM 900 dose-dependently prolonged the sur-vival time of mice exposed to normobaric 97% N2

and 3% O2; the minimum effective IV dose was 10mg/kg.[2]

In an animal model of global cerebral ischaemia(carotid artery occlusion in the gerbil), YM 900 (15or 30 mg/kg IP) markedly prevented delayed neu-

ronal death in the CA1 region. This effect wasmaintained when YM 900 was administered 6h af-ter recirculation.[3]

References1. Umemura K, Kondo K, Ikeda Y, et al. Pharmacokinetics and

safety of the novel amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist YM90K in healthy men. J ClinPharmacol 1997 Aug; 37: 719-27

2. Katoh M, Kawasaki-Yatsugi S, Koshiya K, et al. Anti-convul-sive and anti-hypoxic effects of YM90K, a selective and po-tent AMPA/kainate receptor antagonist. Jpn J Pharmacol1994; 64 Suppl. 1: 207

3. Kawasaki S, Yatsugi S-I, Takahashi M, et al. Postischemic ad-ministration of YM900, a selective and potent alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate receptor antagonist,prevents delayed neuronal death in gerbil hippocampus. JpnJ Pharmacol 1993; 61 Suppl. I: 284P

Table II. Drug development history

Sep-1996 Phase II clinical trials for Stroke in Japan(Injection)

May-1996 Phase II clinical trials for Stroke in Japan(unknown route)

YM 900 43

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