P2‐448: Preclinical evaluation of CDD‐0102, a selective M ₁ agonist with potential utility in Alzheimer's disease

Agonists that selectively activate M1 muscarinic receptors might be useful in treating memory and cognitive deficits, while preventing the formation of amyloid plaques and neurofibrillary tangles associated with Alzheimer's disease. 5-(3-Ethyl-1,2,4-oxadiazol-5-yl)–1,4,5,6-tetrahydropyrimidine trifluoroacetic acid (CDD-0102J) displays functional selectivity for M1 receptors and enhances memory function in animals with cholinergic deficits. The hydrochloride salt (CDD-0102A) also promotes alpha-secretase activity and reverses the apoptotic effects of Abeta in differentiated PC12 cells. CDD-0102A was evaluated in a series of studies to determine pharmacokinetic parameters, drug metabolism and toxicity. Preclinical toxicology studies indicate that CDD-0102A is negative in bacterial mutagenicity, mammalian cell clastogenicity, and mouse micronucleus assays. Moreover, CDD-0102A does not inhibit the HEK-hERG channel current. In a 28-day repeat-dose toxicity study with CDD-0102A in male and female rats, excessive cholinergic stimulation was apparent at high doses yet no overt toxicities were observed. Dogs were more sensitive to CDD-0102A in a comparable study with dose-dependent increased frequency and severity of cholinergic symptoms, although no significant effects on cardiovascular and pulmonary safety parameters were observed. Studies in rats yielded linear pharmacokinetics with dose proportional increases in Cmax and AUC and an estimated t1/2 of 3–5 hr. Comparative drug metabolism studies indicated significant metabolism only in rabbit S9 preparations, with limited metabolism in liver microsomal and S9 preparations from mice, rats, dogs, monkeys and humans. Three potential metabolites were identified from rabbit liver microsomes. The preclinical data are being used in planning Phase I clinical studies of CDD-0102A in healthy adult volunteers. Taken together, the data suggest that CDD-0102A may be useful in treating the symptoms and some of the underlying causes of Alzheimer's disease.