1. Novel Neurotherapeutic
YKP3089
Novel Neurotherapeutic
ASENT
March 2009
Martin Brecher, MD
Life Science
Fair Lawn, New Jersey
New Jersey, U.S.A.
Seoul, Korea
Daejeon, Korea
Shanghai, China

2. YKP3089 Preclinical Summary
Animal Model Profile
Anticonvulsant Profile
Broad spectrum activity in Rat & Mice (i.p., p.o.)
Anxiolytic Profile
Active in diverse AX models in Rat & Mice (i.p., p.o.)
Pain Profile
Potent efficacy in Chung & Bennett models in Rat
Additional Profile
Hypoxia model in Mice
Conditioned Avoidance Rat model

3. Anticonvulsant Profile
YKP3089
Compounds
(Mice, i.p., ED50 mg/kg)
Electrical
Tonic Generalized Seizures
Chemical
Myoclonic/Generalized
Absence Seizures
MES
PTZ
PIC
YKP3089
9.8
28.5
34.5
Lamotrigine
7.5
>40.0
Topiramate
33.0
>800
>500
Phenytoin
6.5
>50
Carbamazepine
9.9
Valproate
287
209
Ethosuximide
>1000
130
Data Source: NIH

4. Anticonvulsant Profile
YKP3089
Compounds
(Rat, ip, ED50 mg/kg)
Refractory epilepsy
Partial Complex
Formation/Progression of Epilepsy
Intractable Seizures
Kindling
Hippocampal
Lithium-pilocarpine intractable seizures
YKP3089
16.4
7.0
Lamotrigine ++ ND
Topiramate -
Phenytoin
+/-
Carbamazepine
Valproate +
Ethosuximide

5. Anticonvulsant Profile
YKP3089
Anticonvulsant Profile
Compounds
(Mice, i.p., ED50 mg/kg)
6 Herz Partial Psychomotor Test
Therapy-Resistant Partial Seizures
22mA
32mA
44mA
YKP3089*
11.0
17.9
16.5
Lamotrigine ND
50% at 20
Phenytoin
58% at 40
Carbamazepine
75% at 40 & 80
Topiramate
>300
Data Source: NIH

6. Fear-Potentiated Startle
Anxiolytic Profile
YKP3089
Effective in a wide variety of anxiety models
Light-Dark Box
Social Interaction
Fear-Potentiated Startle
Marble-Burying
Elevated Plus Maze
Defensive withdrawal, etc.
Active in Rats and Mice
Anxiolytic Test
YKP3089
Buspirone
Light-Dark Box
(Mice, IP)
+++
Social Interaction
(Rat,PO) ++
Fear-Potentiated Startle
(Rat, IP)
Marble-Burying
ED50 <20mg/kg
ED50 <30mg/kg

7. Analgesic (Neuropathic Pain) Profile
YKP3089
Excellent activity in models of neuropathic pain
Improved efficacy compared to gabapentin
Chung Model
Bennett Model
YKP3089
Gabapentin
Mechanical allodynia
+++
Cold allodynia ++
Heat hyperalgesia
ED50 <50mg/kg
ED50 <100mg/kg

8. Additional Indication Profile
YKP3089
Additional Indication Profile
Model
Efficacy
Indication
Hypoxia
(mice, mg/kg, IP) √
Neuroprotective
Conditioned Avoidance
(rat, mg/kg, IP)
Antipsychotic
DOI-Induced Head Twitch
Antipsychotic; Tourette’s
Hippocampal Kindling
Bipolar, Anticonvulsant
Formalin test
Inflammatory pain
Acetylcholine antagonist인 scopolamine을 처리하여 cognition deficit을 유발한
쥐에 YKP3089를 처리한 결과, 10 mg/kg, i.p에서 개체간 차이가 커서 유의하진
않지만 뚜렷한 경향성 (p<0.0665)을 보이면서 memory deficit이 회복됨을 관찰할
수 있었음.
이러한 경향성은, YKP3089가 anti-dementia indication으로 적용가능성이 있음을
시사함.
참고적으로 본 모델은, 대표적인 Alzheimer’s disease의 치료제인 physostigmine
(cholinesterase inhibitor)으로 validate됨.
Stroke와 Dementia는 Parkinson’s disease와 함께, 대표적인 Neurodegenerative
Disease로서, 이들에 YKP3089가 효과를 보이고 있음은, YKP3089가 전반적인
neuroprotection activities를 지닐 가능성이 높음.
YKP509의 경우 역시 MCAO와 같은 Stroke model에선 효과를 보이고 있고,
6-OHDA test와 같은 Parkinson model에서 실험이 완료되었으나 결과는 아직
확보되지 않음.

9. Preclinical ADME/Safety/Toxicity
YKP3089
ADME
Excellent PK parameters
Rat PO
Monkey PO
Good metabolic stability
Moderate plasma protein binding
Good Tissue Distribution
Safety/Toxicity
Good Safety
hERG Channel
Monkey CV Telemetry
Respiratory
Gastric
Negative Gene Toxicity
Typical CNS clinical signs
Low teratogenicity potential
Biological Screen Flow Chart

10. Phase Ia and Ib Clinical Trials (USA)
YKP3089 Clinical Summary
YKP3089
Phase Ia and Ib Clinical Trials (USA)
No clinically significant changes in both single and multiple dose study
ECG
Vital signs
Hematology
Serum chemistry
Urinalysis
YKP3089 shows dose-response relation of clinical signs and adverse events
Excellent PK Parameters
Data suggest once-per-day dosing
YKP3089 is well-tolerated
Adverse events were mild and CNS related

11. YKP3089 Single Dose PK

12. YKP3089 Multiple Dose PK
Both Cmax and AUC linearly correlated with dose
Steady State occurred by Day 12

13. YKP3089 Food Effect Study PK

14. YKP3089 Highlights Efficacy Safety & Toxicity
Potential versatile CNS drug: Epilepsy, Anxiety, Neuropathic Pain, Bipolar Disorder, Dementia, Schizophrenia, etc.
Broad spectrum: Epilepsy
Possible novel mechanism
Safety & Toxicity
High safety margin
Low QTc prolongation potential
Low teratogenic potential
Phase I Clinical Trials in USA
Favorable PK profile
Once a day dosing potential
Low adverse effects