ASCENDING SINGLE DOSE STUDY OF THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACO-DYNAMICS OF SRA-444 ADMINISTERED ORALLY TO HEALTHY ADULT SUBJECTS

Alzheimer disease (AD) is a progressive, neurodegenerative disorder that
accounts for the majority of cases of dementia in the elderly. AD is currently
estimated to afflict 18 million people worldwide, and by 2025 the prevalence is
projected to increase to 34 million1. The therapeutic goal for patients with AD
is to improve memory and cognition, or at least to slow the disease process.
Most current treatments for AD act to modulate neurotransmitter function,
primarily by augmenting cholinergic transmission through inhibition of
acetylcholinesterase
activity. However, these agents have exhibited only modest efficacy, which is
insufficient to reverse or substantially delay cognitive decline in patients
with AD.
Recent preclinical studies have demonstrated a possible role for the serotonin
subtype 1A (5-hydroxytryptamine1A [5-HT1A]) receptors in cognitive function.
These receptors are localized in key brain regions associated with cognition,
mediate events associated with synaptic plasticity, and affect cognitive
performance in animal models. SRA-444
(5-fluoro-8-{4-[4-(6-methoxyquinolin-8-yl)piperazin-1-yl]piperidin-1-yl}quinolin
e tri-succinate) is a selective, potent, full antagonist at the human 5-HT1A
receptor being developed by Wyeth
Research (WR) for the symptomatic treatment of mild to moderate dementia of the
Alzheimer type.

Primary: to assess the safety and tolerability of ascending single oral doses
of SRA-444 in healthy adult subjects

Secondary: to obtain preliminary PK and PD profiles of SRA-444 in healthy adult
subjects to evaluate the effect of a high-fat meal on the PK of SRA-444

a randomized study of ascending single oral doses of SRA-444 to be performed in
8 cohorts of 8 healthy young adult subjects. Part A will be a subject- and
investigator-blinded, placebo-controlled, dose-escalation assessment. Part B
will be an open-label pilot assessment of food effect with a dose previously
tested in part A and expected to be well tolerated.

Single oral doses of SRA-444 ranging from 0.5 mg to 40 mg will be evaluated in
healthy adult subjects after an overnight fast of at least 10 hours. The
following doses will be studied sequentially in ascending order: 0.5 mg, 1 mg,
2.5 mg, 5 mg, 10 mg, 20 mg, and 40 mg.

see flowcharts protocol, page 27-37