- Email: [email protected]
SMALL MOLECULE TAU OLIGOMERIZATION INHIBITORS
P434
Poster Presentations: Sunday, July 24, 2016
models for PK and PK/PD analysis. APP-transgenic mice were 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.
P1-084
SMALL MOLECULE TAU OLIGOMERIZATION INHIBITORS
James G. Moe1, Pavan K. Krishnamurthy2, Patricia Lopez2, Giulia Papiani2, Daisy Romero2, Haiyan Bian3, Mark E. McDonnel3, Allen B. Reitz3, Charles Gluchowski4, Eliot J. Davidowitz2, 1Oligomerix, Inc., Valhalla, NY, USA; 2Oligomerix, Inc., New York, NY, USA; 3Fox Chase Chemical Diversity Center, Inc., Doylestown, PA, USA; 4LifeScience Innovations LLC, Danville, CA, USA. Contact e-mail: jmoe@oligomerix. com Background: Numerous studies have clearly demonstrated the role of tau oligomers in the initiation and progression of tau pathology in Alzheimer’s disease (AD) and associated tauopathies. We have taken a highly differentiated approach to identify novel small molecule inhibitors of tau oligomer formation using proprietary AD relevant in vitro and cell assays, along with the htau mouse model. Here, we present recent progress in the identification of leads for in vivo efficacy and IND enabling studies. Methods: In vitro assays were developed to screen a compound library. Selected candidates identified in the primary screen were subjected to medicinal chemistry studies to identify potential lead compounds after characterization in secondary and cell based assays. A number of lead compounds were also tested in vivo to assess preliminary metabolic stability, pharmacokinetics, off-target activity and acute toxicity. An in vivo study in htau mice will be initiated using vehicle and three doses of a lead. Results: A number of small molecule inhibitors of tau oligomerization with high potency, drug-like properties and with IC50’s in the nanomolar to micromolar range, have been identified. Preliminary metabolic stability using mouse liver microsomes showed a half-life in the range of hours for select compounds. In addition, certain compounds had a brain-plasma distribution of approximately 1:1 and were not toxic when administered daily by i.p. injection to wild type mice for 5 days. Conclusions: From an initial primary screen, we have performed lead optimization
studies which have led to novel tau oligomerization inhibitors with improved properties. P1-085
SUVN-502, POTENT AND PURE 5-HT6 RECEPTOR ANTAGONIST: PROOF-OF-CONCEPT STUDY DESIGN IN MODERATE ALZHEIMER’S DISEASE PATIENTS
Ramakrishna Nirogi, Koteshwara Mudigonda, Kiran Kumar Penta, Gopinadh Bhyrapuneni, Vijay Benade, NageswaraRao Muddana, Veera Raghava Chowdary Palacharla, Devender Reddy Ajjala, Vinod Kumar Goyal, Santosh Kumar Pandey, Renny Abraham, Pradeep Jayarajan, Ramasastry Kambhampati, Anil K. Shinde, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: [email protected] Background: SUVN-502 is a pure 5-HT6receptor antagonist. It has
good ADME properties and demonstrated robust efficacy in preclinical studies. SUVN-502 has excellent margin of safety in long-term preclinical toxicity studies. In healthy human subjects, SUVN-502 was well tolerated following single or multiple oral administrations. There were no clinically relevant or serious adverse events. Methods: The effect of SUVN-502 alone and in combination with memantine and donepezil was evaluated in object recognition task. SUVN-502 was also evaluated in combination with donepezil and memantine on hippocampal acetylcholine levels in awake rats and on local field potential responses to electric stimulation of the brain stem in anesthetized rats. Exposures of SUVN-502 and active metabolite M1 of SUVN-502 required to show efficacy in Alzheimers disease (AD) patients was projected based on the efficacy outcome and CNS penetration in animal models. Results: Cotreatment of SUVN-502 with memantine and donepezil significantly potentiated the procognitive effects when compared with memantine and donepezil treatment group. These effects were seen even after repeated treatment for 14 days. SUVN-502 potentiated the effects of donepezil and memantine, in hippocampal acetylcholine levels and brain oscillatory activity. There were no significant changes in the exposures of SUVN-502 or donepezil or memantine. SUVN-502 and M1 of SUVN-502 achieved the projected efficacy concentrations and attained steady state on day 7 upon multiple administrations in elderly subjects. SUVN-502 has favorable pharmacokinetics suitable for once a day oral administration. Conclusions: The enhanced procognitive effects seen in the group co-treated with SUVN-502, memantine and donepezil can be attributed to the augmentation of the cholinergic neurotransmission in the brain. Thus combination of SUVN-502 with memantine and donepezil may offer a novel therapeutic strategy for the symptomatic treatment of AD. SUVN-502 is being evaluated in moderate AD patients currently treated with donepezil and memantine. A total of 537 subjects aged between 50 to 85 years are being enrolled.
P1-086
THE DRUG TG REDUCING BACE1 EXPRESSION LEVEL AND PREVENTING COGNITIVE IMPAIRMENT IN ALZHEIMER’S DISEASE MICE
Seung Hyun Baek, Bo Youn Choi, Yoonsuk Cho, HarkKyun Kim, Gun Young Jung, Hee Jin Park, Jihoon Han, Gahee Bahn, Dong-Gyu Jo, Sungkyunkwan University, Suwon-si, The Republic of Korea. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) has characterized neuro-
pathological hallmark. Soluble amyloid beta generated from amyloid precursor protein by beta- and gamma-secretase induces neuronal dysfunction and cell death. A key neuropathological event in AD is the cerebral accumulation of senile plaques formed by
Poster Presentations: Sunday, July 24, 2016
models for PK and PK/PD analysis. APP-transgenic mice were 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.
P1-084
SMALL MOLECULE TAU OLIGOMERIZATION INHIBITORS
James G. Moe1, Pavan K. Krishnamurthy2, Patricia Lopez2, Giulia Papiani2, Daisy Romero2, Haiyan Bian3, Mark E. McDonnel3, Allen B. Reitz3, Charles Gluchowski4, Eliot J. Davidowitz2, 1Oligomerix, Inc., Valhalla, NY, USA; 2Oligomerix, Inc., New York, NY, USA; 3Fox Chase Chemical Diversity Center, Inc., Doylestown, PA, USA; 4LifeScience Innovations LLC, Danville, CA, USA. Contact e-mail: jmoe@oligomerix. com Background: Numerous studies have clearly demonstrated the role of tau oligomers in the initiation and progression of tau pathology in Alzheimer’s disease (AD) and associated tauopathies. We have taken a highly differentiated approach to identify novel small molecule inhibitors of tau oligomer formation using proprietary AD relevant in vitro and cell assays, along with the htau mouse model. Here, we present recent progress in the identification of leads for in vivo efficacy and IND enabling studies. Methods: In vitro assays were developed to screen a compound library. Selected candidates identified in the primary screen were subjected to medicinal chemistry studies to identify potential lead compounds after characterization in secondary and cell based assays. A number of lead compounds were also tested in vivo to assess preliminary metabolic stability, pharmacokinetics, off-target activity and acute toxicity. An in vivo study in htau mice will be initiated using vehicle and three doses of a lead. Results: A number of small molecule inhibitors of tau oligomerization with high potency, drug-like properties and with IC50’s in the nanomolar to micromolar range, have been identified. Preliminary metabolic stability using mouse liver microsomes showed a half-life in the range of hours for select compounds. In addition, certain compounds had a brain-plasma distribution of approximately 1:1 and were not toxic when administered daily by i.p. injection to wild type mice for 5 days. Conclusions: From an initial primary screen, we have performed lead optimization
studies which have led to novel tau oligomerization inhibitors with improved properties. P1-085
SUVN-502, POTENT AND PURE 5-HT6 RECEPTOR ANTAGONIST: PROOF-OF-CONCEPT STUDY DESIGN IN MODERATE ALZHEIMER’S DISEASE PATIENTS
Ramakrishna Nirogi, Koteshwara Mudigonda, Kiran Kumar Penta, Gopinadh Bhyrapuneni, Vijay Benade, NageswaraRao Muddana, Veera Raghava Chowdary Palacharla, Devender Reddy Ajjala, Vinod Kumar Goyal, Santosh Kumar Pandey, Renny Abraham, Pradeep Jayarajan, Ramasastry Kambhampati, Anil K. Shinde, Suven Life Sciences Ltd, Hyderabad, India. Contact e-mail: [email protected] Background: SUVN-502 is a pure 5-HT6receptor antagonist. It has
good ADME properties and demonstrated robust efficacy in preclinical studies. SUVN-502 has excellent margin of safety in long-term preclinical toxicity studies. In healthy human subjects, SUVN-502 was well tolerated following single or multiple oral administrations. There were no clinically relevant or serious adverse events. Methods: The effect of SUVN-502 alone and in combination with memantine and donepezil was evaluated in object recognition task. SUVN-502 was also evaluated in combination with donepezil and memantine on hippocampal acetylcholine levels in awake rats and on local field potential responses to electric stimulation of the brain stem in anesthetized rats. Exposures of SUVN-502 and active metabolite M1 of SUVN-502 required to show efficacy in Alzheimers disease (AD) patients was projected based on the efficacy outcome and CNS penetration in animal models. Results: Cotreatment of SUVN-502 with memantine and donepezil significantly potentiated the procognitive effects when compared with memantine and donepezil treatment group. These effects were seen even after repeated treatment for 14 days. SUVN-502 potentiated the effects of donepezil and memantine, in hippocampal acetylcholine levels and brain oscillatory activity. There were no significant changes in the exposures of SUVN-502 or donepezil or memantine. SUVN-502 and M1 of SUVN-502 achieved the projected efficacy concentrations and attained steady state on day 7 upon multiple administrations in elderly subjects. SUVN-502 has favorable pharmacokinetics suitable for once a day oral administration. Conclusions: The enhanced procognitive effects seen in the group co-treated with SUVN-502, memantine and donepezil can be attributed to the augmentation of the cholinergic neurotransmission in the brain. Thus combination of SUVN-502 with memantine and donepezil may offer a novel therapeutic strategy for the symptomatic treatment of AD. SUVN-502 is being evaluated in moderate AD patients currently treated with donepezil and memantine. A total of 537 subjects aged between 50 to 85 years are being enrolled.
P1-086
THE DRUG TG REDUCING BACE1 EXPRESSION LEVEL AND PREVENTING COGNITIVE IMPAIRMENT IN ALZHEIMER’S DISEASE MICE
Seung Hyun Baek, Bo Youn Choi, Yoonsuk Cho, HarkKyun Kim, Gun Young Jung, Hee Jin Park, Jihoon Han, Gahee Bahn, Dong-Gyu Jo, Sungkyunkwan University, Suwon-si, The Republic of Korea. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) has characterized neuro-
pathological hallmark. Soluble amyloid beta generated from amyloid precursor protein by beta- and gamma-secretase induces neuronal dysfunction and cell death. A key neuropathological event in AD is the cerebral accumulation of senile plaques formed by