Introduction on Drug Research and Development(R D) Process in the USa
Introduction on Drug Research and Development (R & D) Process in the USA 1
“Rock” Diagram of Drug Development Process Targets Toxicology IND Screens|→ Selection IⅢ NDA Pharmaco kinetics SAR 2,000 cpds 20 year 50 Mill 50 100200400 800 Discovery Pre-clinical Clinical Marketing 2
“Rock” Diagram of Drug Development Process Targets Scrrens SAR Discovery Pre-clinical Clinical Marketing I II III Toxicology Pharmacokinetics Selection NDA IND 2,000 cpds 20 6 3 2 1 1 year 1 1 2 3 50 Mill 50 100 200 400 800 2
Drug Development Process 11. Discovery stage (2). Pre-clinical Stage (3). Clinical Stage (4). Marketing Stage 3
Drug Development Process (1). Discovery Stage (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 assay development and validation Automation Optimization Compound library High throughput screens ∫ Combinatorial chemistry Library chemistry Natural products Lead confirmation and chemistry Preliminary pK investigation SAR In vivo functional tests
Major Steps in Discovery Stage Target generation and selection Compound Library Combinatorial chemistry Library chemistry Natural products { Development Method set-up Method validation Technique assesment Automation Optimization } High throughput screens Lead confirmation and chemistry In vivo functional tests Assay development and validation Preliminary PK investigation SAR 4
Target Generation and Selection Target Target Target as Target based on associated mechanism causing hypothesis with disease of disease disease Schizophrenia Alzheimer P arkinson Genetics (DA in Pfc (Aβ-42) DA in Striatum) (Disease genes) Copying others (Fluoxetine and Screening arket analysis olanzapine stories)
Target Generation and Selection Screening Target based on hypothesis Target associated with disease Target as mechanism of disease Target causing disease Copying others (Fluoxetine and olanzapine stories) Schizophrenia Alzheimer Parkinson Genetics (DA in Pfc) (Ab-42) (DA in Striatum) (Disease genes) Market Analysis 5
Structure of olanzapine and other Anti-psychotics CH, CHa CH3 Risperidone Clozapine HOH H B C Ha Olanzapine CH Remoxipride Seroquel
Structure of Olanzapine and Other Anti-psychotics 6
Structure of Fluoxetine and other Anti-depressants Fluoxetine OCHCH2CH2NHCH. Zimelidine Fluvoxamine U。 CFa CHCH2CH2CH2OCHa HCCH2N(CHa) N-OCH2CH2NHz Citalopram CH,CH,CH2N(CH3)2 Paroxetine Sertraline <1。ya∈ NHCHa
Structure of Fluoxetine and Other Anti-depressants 7
Developments of Anti-depressants O. 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) D 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 mechanism (I. Non-monoamine related drugs (1). NK-1 antagonists AprpitantMK-869, L-754030, stopped) (2). PDE4 inhibitors MEM 1414 (preclinical (3). CRF1 antagonists Many compounds (4). Other mechanisms St John's wort
Developments of Anti-depressants (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 Aprpitant (MK-869, L-754030, stopped) (2). PDE4 inhibitors MEM 1414 (preclinical) (3). CRF1 antagonists Many compounds (4). Other mechanisms St John’s Wort 8
Problems with Current Anti-depressants Limitations in efficacy Efficacy between currently antidepressants and TCAs 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 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)
Problems with Current Anti-depressants Limitations in efficacy • Efficacy between currently antidepressants and TCAs 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 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) 9
Combinations of SSRIs and 5-HT1A Antagonists WAY SSRI (-) 5-HTIA ypothesis Combination of ssri and (-) TRYP 5-HTP5-HT 5-HT 5-HTA antagonist may overcome the delayed onset of anti-depressant action of ssris
Combinations of SSRIs and 5-HT1A Antagonists 5-HT SSRI T 5-HTP 5-HT 5-HT1A TRYP (-) WAY (-) (-) Hypothesis: Combination of SSRI and 5-HT1A antagonist may overcome the delayed onset of anti-depressant action of SSRIs 10