Premium
P1‐085: SUVN‐502, Potent and Pure 5‐HT 6 Receptor Antagonist: Proof‐of‐Concept Study Design in Moderate Alzheimer’s Disease Patients
Author(s) -
Nirogi Ramakrishna,
Mudigonda Koteshwara,
Penta Kiran Kumar,
Bhyrapuneni Gopinadh,
Benade Vijay,
MuddageswaraRao,
Chowdary Palacharla Veera Raghava,
Ajjala Devender Reddy,
Goyal Vinod Kumar,
Pandey Santosh Kumar,
Abraham Renny,
Jayarajan Pradeep,
Kambhampati Ramasastry,
Shinde Anil K.
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.833
Subject(s) - donepezil , memantine , pharmacology , adverse effect , antagonist , medicine , pharmacokinetics , neuropharmacology , acetylcholinesterase inhibitor , psychology , acetylcholinesterase , dementia , receptor , disease , chemistry , biochemistry , enzyme
used for chronic efficacy studies. Results: CNP520 is selective for BACE-1 over BACE-2 and highly selective over pepsin, cathepsin D & E, and renin. Low nanomolar inhibition of Ab and sAPPb release was observed in cell assays using wt-APP cells. The free fraction of CNP520 in the rat brain, and the concentration of CNP520 in the CSF, was comparable to unbound blood concentrations, indicating excellent brain penetration. Oral dosing of CNP520 reduced Ab in the rat brain by more than 80%. A single CNP520 dose in dogs reduced CSF Ab for 72 hours, in agreement with long terminal half-lives (9.5-23 hours) in animals. CNP520 did not induce any hair depigmentation when dosed to mice for 8 weeks at a dose for > 90% Ab reduction. No hypopigmentation was observed in chronic studies in transgenic mice, and during long-term toxicology studies. CNP520 was dosed into APP23 mice 6 months and showed dose-dependent reduction of Triton TX-100 soluble and insoluble Ab. At the high dose, the levels of deposited Ab40/42 were indistinguishable from baseline. Conclusions: Preclinical data predict that more than 80% Ab reduction can be reached in humans at steady state. CNP520 stopped further amyloid-b deposition in APP transgenic mice, indicating that the compound may be able to show long term efficacy against Ab deposition in humans.