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| Type |
Oral Presentation |
| Area |
Oral Presentation of Young Discovery Chemists |
| Room No. |
Room 304 |
| Time |
THU 09:45-10:00 |
| Code |
MEDI.O-4 |
| Subject |
Novel tau aggregation inhibitors for treatment of Alzheimer’s Disease |
| Authors |
WooSeung Son, Sang Min Lim1, Kyu-Sung Jeong, Ae Nim Pae1,*
Department of Chemistry, Yonsei University, Korea
1Convergence Research Center For Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Korea
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| Abstract |
Alzheimer’s disease(AD) is a chronic neurodegenerative disease that is the most common form of dementia. It is still unknown what AD causes, but AD features two histopathological hallmarks : amyloid plaques(AP) made of amyloid-β and neurofibrillary tangles(NFTs) arising from the hyperphosphorylated tau aggregation in pathology. It is known AP and NFT are neurotoxic that may lead to impairment of brain. In clinical trials, diverse compounds, such as amyloid aggregation inhibitors, β-secretase inhibitors and so on, have been failed to cure AD patients. Therefore, our rationale of tau aggregation inhibitors reduce the generation of NFT that may relate to causes of AD. We identified lead compound (DTC0100) which inhibits tau aggregation by high contents screening in Tau Bi-FC cell-based assays. Then, a variety of derivatives were synthesized through a structure-activity relationship study and the optimization of novel tau aggregation inhibitors to improve potency, physicochemical properties and in vivo efficacy. Among synthesized compounds, DTC0521 showed excellent inhibitory activity of tau aggregation (IC50 = 0.06 µM) in Tau Bi-FC assays and was also lower tau aggregation (IC50 = 0.58 µM) in ThS assays. DTC0521 showed the recovery of cognitive impairments (Tau-P301L-BiFC transgenic mice) in behavior test and decreases tau aggregation as well as phosphorylated tau. It also exhibited good pharmacokinetic profile and ADME/Tox, thus, the validation of DTC0521 as preclinical candidate and further optimization are in progress. |
| E-mail |
214012@kist.re.kr |
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123rd General Meeting of the KCS