PRECLINICAL AND PHASE-1 CLINICAL CHARACTERIZATION OF CI-979 RU35926, A NOVEL MUSCARINIC AGONIST FOR THE TREATMENT OF ALZHEIMERS-DISEASE/

In vitro and in vivo characterization in rodents and monkeys shows tha t CI-979/RU35926 is a partial muscarinic agonist with equal affinity f or the five subtypes of muscarinic receptors. It activates central cho linergic receptors as shown by its ability to decrease body temperatur e, enhance local cortical blood flow and increase cortical arousal mea sured by QEEG. Further, it reverses spatial memory deficits in rats wi th ibotenic acid-induced lesions of forebrain cholinergic neurons. Sig ns of peripheral cholinergic stimulation appear at doses higher or equ al to those necessary to produce central activity. In a single-dose to lerance study in young, healthy human volunteers, CI-979/RU35926 was w ell tolerated at doses of 0.002-1.0 mg with cholinergic symptoms such as hypersalivation and sweating, observed at 2-4 mg. It demonstrated l inear pharmacokinetic behavior over a dose range of 0.1 to 4 mg and el imination half-life varied from 2-5 hours. Measurement of unchanged dr ug in urine suggests that the drug was extensively metabolized. Thus, the safety profile supported further clinical evaluation and CI-979/RU 35926 is currently in Phase II clinical trials.