药物研究与开发(英文ppt)

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Assay development and validation
High throughput screens
{
Compound Library Combinatorial chemistry Library chemistry Natural products
Lead confirmation and chemistry
Preliminary PK investigation
SAR
In vivo functional tests
4
Target Generation and Selection
Target based on hypothesis
Target associated with disease
Target as mechanism of disease
10
Multiple Possibilities for the Development of New Anti-depressants
WAY
(-) 5-HT1A 5-HT1B (-) (-) T (-) TRYP 5-HTP 5-HT 5-HT (-) (+) E G 5-HT3 ATP cAMP DA DA (+)
Introduction on
Drug Research and
Development (R & D) Process in the USA
1
“Rock” Diagram of Drug Development Process
Targets
Toxicology IND I
Scrrens
Pharmacokinetics
Selection
II
III
NDA
SAR
2,000 cpds 20 6 3 2 1
1 year
50 Mill Discovery
1
50 Pre-clinical
1
2
3
800 Marketing
2
100 200 400 Clinical
Drug Development Process
(1). Discovery Stage
1 day 1 wk 4 wks 12 wks 6 mons 12 mons 2 years Rat Mouse Dog Monkey 2 – 4 doses Usually oral, but sometimes ip, iv To determine NOAEL, motility, clinical pathology, histopathology, etc. 15
9
Combinations of SSRIs and 5-HT1A Antagonists
WAY
(-) 5-HT1A (-) T (-) TRYP 5-HTP 5-HT 5-HT
SSRI
Hypothesis:
Combination of SSRI and 5-HT1A antagonist may overcome the delayed onset of anti-depressant action of SSRIs
TCAs • Anti-cholinergic side effects • CV side effects and orthostatic hypotension
SSRIs • Nausea, headache, insomnia, agitation and sexual dysfunction, etc. • Delayed onset of actions MAOs • Hypertensive crisis
(I). Monoamine related drugs (A). Monoamine uptake inhibitors (1). Selective 5-HT uptake inhibitors (SSRIs) Astra Zimeldine (Withdrawn in 83) Lilly Fluoxetine (Prozac) Pfizer Sertraline (Zoloft) GSK Paroxetine (Paxil) Forest/Lundberg Citalopram (Celexa) (2). Selective NE uptake inhibitors (SNRI) Reboxetine (3). Selective DA uptake inhibitors Nomifensine (4). Dual 5-HT/NE uptake inhibitors Duloxetine (Cymbalta) (5). Dual DA/NE uptake inhibitors Bupropion (6). Non-selective reuptake inhibitors: Tricyclic (TCAs): imipramine, desipramine, etc. (B). Auto-receptor inhibitors to achieve rapid onset of actions (1). 5-HT1A antagonists Pindolol (2). a2-adrenoceptor antagonists Napamezole (C). Neurotransmitter releaser Fenfluramine (D). Monoamine oxidase inhibitors (MAOI) Resagerine (E). Specific receptors agents (1). 5-HT receptors Buspirone (5-HT1A partial agonist) (2). NE receptor agent Modafinil (a1-adrenoceptor agonist) (F). Combinations of SSRI with other mechanisms (II). Non-monoamine related drugs (1). NK-1 antagonists (2). PDE4 inhibitors (3). CRF1 antagonists (4). Other mechanisms
Aprpitant (MK-869, L-754030, stopped) MEM 1414 (preclinical) Many compounds St John’s Wort
8
Problems with Current Anti-depressants
Limitations in efficacy • Efficacy between currently antidepressants and TCAs
13
Major Steps in Pre-clinical Stage
General pharmacological studies
• Effects on various systems for safety evaluation
Comprehensive PK studies
• Absorption, distribution, metabolism and excretion (ADME)
Drug Development Process
(1). Discovery Stage
Target causing disease
Schizophrenia
(DA in Pfc)
Alzheimer
(Ab-42)
Parkinson
(DA in Striatum)
Genetics
(Disease genes)
Copying others
(Fluoxetine and olanzapine stories)
Screening
Market Analysis
5
Structure of Olanzapine and Other Anti-psychotics Nhomakorabea6
Structure of Fluoxetine and Other Anti-depressants
7
Developments of Anti-depressants
Napamezole Bupropion
SSRI
Anti-depressant Actions
5-HT?
NE
NE
a1
a2 (-)
(-) 5-HT1D
11
Animal Models for Depression Studies
Learned helplessness (increase escape behavior) Forced swim/behavioral despair (increase the latency) Tail suspension test (increase the latency) Chick isolation (increase the latency) Olfactory bulbectomy (increase learning and memory) Differential reinforcement of low rates of response (DRL) 5-HTP induced head twitch (increase response) Aggression behaviors (attenuate aggression)
Formulation development
• Further improve PK profiles of the final candidates
Scale-up and stability
• Prepare large quantity of the compounds for safety studies
Acute and chronic animal toxicological studies
14
Pre-clinical Safety and Toxicological Studies
(A). Safety Pharmacology Studies (1) General pharmacology on major systems (2) CNS safety (3) CV safety hERG, APD, anaethetized dog, dog telemetric study (4) GI motility (5). Genetic Cytogenicity, Ames, mutagenic, etc. (B). Toxicology Studies (1). Study duration Acute Chronic (2) Animal species (3) Doses (4) Administration route (5) Goals
(2). Pre-clinical Stage (3). Clinical Stage (4). Marketing Stage
3
Major Steps in Discovery Stage
Target generation and selection
Development Method set-up Method validation Technique assesment Automation Optimization
Amphetamine self-administration (reduce response)
Activity wheel stress (reduce response)
12
Drug Development Process
(1). Discovery Stage
(2). Pre-clinical Stage (3). Clinical Stage (4). Marketing Stage
Weight gain • Weight gain could be a sign of improvement in depressive symptoms • TCAs and MAOs are likely to cause weight gain than SSRIs • Paroxetine may be more likely to cause weight gain (3.6% in 6 months)