Key points are not available for this paper at this time.
Cognitive decline and anxiety are clinical symptoms of Alzheimer's disease. Dimebon, developed by Medivation, Inc. and Pfizer, is in Phase III trials to treat Alzheimer's disease. However, it has multiple liabilities, especially regarding DMPK, and very limited pre-clinical data. More than 10,000 compounds from the ChemDiv, Inc. proprietary library were screened on a panel of GPCRs reportedly involved in the pathophysiology of Alzheimer's disease. Several hits were tested in in vitro and in vivo models and optimized on a smaller panel of GPCRs, including the serotonin receptor 5-HT6. Radioligand binding and cell-based functional assays were used to determine the selectivity and specificity of lead candidates. Preclinical ADME and behavioral studies comparing our lead compounds with Dimebon and other cognitive-enhancing compounds were performed in mice and rats. Additional safety studies were performed in rabbits, guinea pigs, dogs and monkeys. A dose-escalation Phase I study in healthy volunteers was completed. A Phase II study has been initiated. Optimization of lead compounds resulted in drug candidate AVN-101. Its chemical synthesis, physico-chemical properties, metabolism, molecular pharmacology, pharmacokinetics, in vivo efficacy in behavioral models and safety profile will be presented. Both the molecular pharmacological properties and in vivo efficacy of AVN-101 are similar to those of Dimebon. Scopolamine- and MK-801-induced cognitive dysfunction was restored by AVN-101 in all behavioral tests. Additionally, AVN-101 had similar or better efficacy compared to clinically used anxiolytics in animal models. AVN-101 showed superior efficacy over Dimebon in most behavioral tests. In Phase I studies AVN-101 was very well tolerated in 32 healthy volunteers. The harmonic mean half life reached 14 hours with a linear increase of Cmax and AUC in the dose range from 2 to 20 mg given orally. Phase II studies of once-a-day oral dosing of AVN-101 are ongoing for anxiety and in planning for Alzheimer's disease. The PK profile of AVN-101 has a clear superiority over that of Dimebon. Overall, AVN-101 is a promising, new drug candidate to treat Alzheimer's Disease.
Lavrovsky et al. (Thu,) studied this question.