Alzheimer's disease (AD) is a progressive and ultimately fatal neurodegenerative disease that affects more than five million people in the USA. Currently there is no cure for AD. Available medicines are aimed only at temporarily reducing symptoms and slowing down the progression of the disease. While many new compounds have been developed to treat AD, they have not been successful in clinical studies and consequently there is a great need for development of new therapeutic strategies. Recent data show that retinoic acid (RA) plays an important role in maintaining neuronal plasticity, and learning and memory in human or in transgenic animal model of AD, and support our hypothesis that increasing RA in the brain will improve AD patient outcomes. However, RA has poor pharmacokinetics in humans and it induces its own clearance resulting in loss of activity during long-term use. In this STTR effort, Dermaxon will use inhibition of RA clearance, instead of treatment with RA itself as a novel therapeutic strategy to treat or prevent progression of cognitive impairments associated with AD. The clearance of RA is predominantly mediated by cytochrome P450 family 26 enzymes (CYP26) of which there are three isoforms: CYP26A1, CYP26B1 and CYP26C1. While CYP26A1 appears to be the human liver RA hydroxylase, CYP26B1 is predicted to be responsible for RA metabolism in extrahepatic tissues and CYP26C1 appears to prefer 9cis-RA as a substrate. In preliminary studies, different chemotypes with a nanomolar IC50 at CYP26A1 and/or CYP26B1 have been identified. Such a novel class of compounds is expected to be highly specific for the different CYP26 isoforms, thereby avoiding side effects and non-target P450 inhibition associated with previously described CYP26 inhibitors. Dermaxon's goal is to develop the next generation of novel selective inhibitors of CYP26, to increase RA concentration in the brain, and to treat memory impairment associated with AD. Using our previously discovered lead structures, we will first generate a series of new compounds with improved CYP26 inhibition potency and selectivity. We will then evaluate their pharmacokinetic properties in mice as well as their efficacy in rescuing memory deficits in the AD mouse model PS1-APP. By the end of this Phase I STTR, Dermaxon will have identified a candidate compound that selectively targets CYP26B1 and also provide evidence that these compounds exhibit in vivo efficacy in rescuing the memory deficit in AD mouse model. In the Phase II of this STTR project we will initiate FDA discussions and complete pre-clinical studies required to file an Investigational New Drug Application (IND) to initiate clinical studies.
Demaxon has outlined a strategy for developing novel inhibitors of CYP26 enzymes that are responsible for the clearance of retinoic acid, as a therapeutic approach to improve learning and memory in Alzheimer's disease patients. In America alone, more than five million patients currently suffer from Alzheimer's disease or some form of dementia and this figure is expected to jump to 13.8M by 2050 with the associated cost of long- term care services reaching $1.2 trillion a year. The outcome of this STTR Phase I will validate CYP26 as druggable target for the treatment of neurodegenerative disease and generate data necessary to develop the most promising CYP26 inhibitor as a new approach to treating Alzheimer's disease.
|Brindisi, Margherita; Maramai, Samuele; Gemma, Sandra et al. (2016) Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain. J Med Chem 59:2612-32|
|Diaz, Philippe; Huang, Weize; Keyari, Charles M et al. (2016) Development and Characterization of Novel and Selective Inhibitors of Cytochrome P450 CYP26A1, the Human Liver Retinoic Acid Hydroxylase. J Med Chem 59:2579-95|
|Foti, Robert S; Isoherranen, Nina; Zelter, Alex et al. (2016) Identification of Tazarotenic Acid as the First Xenobiotic Substrate of Human Retinoic Acid Hydroxylase CYP26A1 and CYP26B1. J Pharmacol Exp Ther 357:281-92|
|Foti, Robert S; Diaz, Philippe; Douguet, Dominique (2016) Comparison of the ligand binding site of CYP2C8 with CYP26A1 and CYP26B1: a structural basis for the identification of new inhibitors of the retinoic acid hydroxylases. J Enzyme Inhib Med Chem 31:148-161|