Topic 1 - The drug discovery process: general principles and some case histories

• drug discovery - from therapeutic concept to molecule

• drug development - from molecule to registered product

• commercialization - from product to therapeutic application to sales

3 main phases of creating a new drug

• Target selection

• Target validation

• Lead finding

• Lead optimization

The discovery phase includes these stages

• Preclinical development

• Clinical development

• Regulatory approval

The development phase includes these stages

1. Targets (receptors or enzymes)

2. Disease

3. Molecules (compound library

Target selection is the finding of a perfect molecule. It could start with

Target validation

Means to validate target; undergoes screening/assays

Lead finding

Means finding lead compound; uses softwares or technology

Lead optimization

Discovery phase where there already is a candidate drug

true

Development phase is not a linear process, it takes about 10 years

True or false

Branded drugs = discovery, development, commercialization

Generic drugs = development, commercialization

Branded drugs are expensive since it undergoes stages from ____, while generic drugs only undergo _____

1. HTS

2. SAR

3. Molecular docking

Softwares used in screening

HTS

This software used in screening is used to fine tune a drug. It is a special computer equipment

SAR (structural activity relationships)

This software used in screening has something to do with structure of molecules and how it acts

Molecular docking

This software used in screening finds receptors where molecules highly fit. Molecules in 3D are being docked

Distribution, metabolism, pharmacokinetic

DMPK means

1. Small molecules

2. Biopharmaceuticals

3. Natural products

Sources of drugs

biopharmaceuticals

Source of drugthat includes endogenous substances (comes from humans, within the body) optimized and made better. E.g., trastuzumab

Natural products

Source of drug that are therapeutic agents originating from nature (plants, microbes, and animals). Historically much of the pharmacopoeia are from these

speedups

Refers to the time from project start to the compound shrank (often less than or equal to 3 years post target selection via HTS, automated synthesis and modeling)

Front loading

Earlier DMPK/tox screens reduce late attrition

1960 to 1980

This period was actually highly productive in terms of drug discovery, representing a return on R and D investment

Defined molecular targets

This is the necessary starting point for drug discovery, and turn automatically to molecular technologies to provide the necessary tools

Biopharmaceutical agents

Are very diverse, including endogenous mediaters, monoclonal antibodies and vaccines, and in the future, no doubt, products for siRNA and gene therapy application

Natural products

Therapeutic agents, particularly anti-infective and anti-tumour drugs originate from these products rather than synthetic molecules

1950

This period is when synthetic chemistrry really came into its own as a source of new drugs, most of the pharmacopoeia consisted of natural products, and they continue to be important

artemesinin

Anti-malarial drug

• Ciclosporin fujimycin (FK506)

• rapamycin

• paclitaxel

Immunosuppressant

epothilones

Anticancer drugs

Drug discovery phase of a typical project aimed at producing a new synthetic drug

warfarin

Example of therapeutic drug derived from natural product

• Anticoagulant. Synthetic compound derived from dicoumarol, found in spoiled sweet clover

dicoumarol

Warfarin is a synthetic compound derived from this which is found in spoiled sweet clover

heparin

Example of therapeutic drug derived from natural product

• Anticoagulant, occurring naturally in mammalian tissues

Hirudin

Example of therapeutic drug derived from natural product

• Anticoagulant from leech, now produced by genetic engineering

• Warfarin

• Heparin

• Hirudin

Examples of therapeutic drugs derived from natural products that are anticoagulants

opiates

Example of therapeutic drug derived from natural product

• Analgesic compound from poppies

Methylxanthines (caffeine, theophylline)

Example of therapeutic drug derived from natural product

• Phosphodiesterase inhibitors and adenosine receptor antagonists. Produced by tea, coffee and coca plants

statins

Example of therapeutic drug derived from natural product

• HMG CoA reductase inhibitors used to reduce plasma cholesterol

Lovastatin (statins)

Example of therapeutic drug derived from natural product

• Is a fungal metabolite

(statins)

• Mevastatin

• pravastatin

Example of therapeutic drug derived from natural product

• Compounds synthesized from lovastatin

cromoglycate

Example of therapeutic drug derived from natural product

• Asthma prophylaxis. Synthetic compound based on khellin, a plant product used as a herbal medicine

Vinca alkaloids (vincristine, vinblastine)

Example of therapeutic drug derived from natural product

• Anticancer drugs produced by plants of the periwinkle family

paclitaxel

Example of therapeutic drug derived from natural product

• Anticancer drug from yew tree

etoposide

Example of therapeutic drug derived from natural product

• Anticancer drug synthesized from podophyllotoxin, produced by mandrake plant; used in folk medicine

Artemether

Example of therapeutic drug derived from natural product

• Antimalarial drug, semisynthetic derivative of artemesin, produced by Chinese herb

Ivermectin

Example of therapeutic drug derived from natural product

• Antihelminthic drug semisynthetic derivative of avermectin, a fungal metabolite

antibiotics

Example of therapeutic drug derived from natural product

• Too numerous to list. The majority of current ___ are derived from fungal metabolites

• Opiates

• Atropine

• Ephedrine

• Ergot alkaloids

• Strychnine

• Tubocurarine

• Digoxin

• Quinine

• Veratidine

• Reserpine

In earlier times the pharmacopoeia consisted very largely of plant-derived compounds, many of which remain in therapeutic use or provide valuable research tools

Discovery pathways of some successful projects

Natural product inhibitor of tubulin depolymerization

Paclitaxel (Taxol) MOA

US National Cancer Institute/Bristol Myers Squibb

Paclitaxel (Taxol) was developed by the company

Ovarian cancer

Paclitaxel (Taxol) indication

1964

Paclitaxel (Taxol) project started in

1971 (7 years from when the project started)

The year Paclitaxel (Taxol)’s compound was synthesized or its structure determined

1983 (19 years)

Paclitaxel (Taxol) phase 1 started in

1992 (28 years)

Year Paclitaxel (Taxol) was registered

1962

1969

To create Paclitaxel (Taxol), the sample bark from the Pacific Yew was collected in ___ and found to have modest activity against various tumour cell lines. The active substance was isolated in ___

1. Paclitaxel is insoluble in water and early formulations for injections used in Phase 1 trials contained high proportion of the solubilizing agent Cremophor EL (causes severe allergic reactions when given as a bolus IV)

2. Supply material for clinical trials and the uncertainty that it could ever be produced on a commercial basis

Development of Paclitaxel (Taxol) was difficult for 2 main reasons

baccatin

Commercialization of the material (Paclitaxel) extracted from the Pacific Yew bark was seen as a major problem, but it was solved when the needles of many yew species contain this, from which paclitaxel can be produced

1999

Synthetic Paclitaxel was officially approved in

1. Failure of the primary screen to reveal the compound as anything out of the ordinary

2. Appearance of serious side effects resulting from the properties of the excipient

3. Supply problem

Obstacles to progress in Paclitaxel include

Antidysrhythmic drug. Blocks cardiac Na+ channels

Flecainide (Tambocor) MOA

3M

Flecainide (Tambocor) was developed by the company

Cardiac dysarhythmias

Flecainide (Tambocor) indication

1965

Flecainide (Tambocor) project started in

1974 (9 years from when the project started)

Flecainide (Tambocor)’s compound was synthesized or its structure determined in

1976 (11 years)

Flecainide (Tambocor) phase 1 started in

1984 (19 years)

Flecainide (Tambocor) was registed in

• Quinidine

• Procainamide

• Digoxin (for supraventricular tachyarhythmias)

• lidocaine (given i.v. for ventricular dysarhythmias)

In the early 1960s, the drugs used to treat cardiac dysarhythmias were mainly

true

In Flecainide (Tambocor) project,

• primary screening assay was based on the ability of compounds to prevent ventricular fibrillation induced by chloroform inhalation in mice

• Secondary assays on selected compounds were carried out on anesthesized dogs

True or false

Flecainide (Tambocor)

Was the first deliberate effort to develop an improved antidysrhythmic drug and proved highly successful in the clinic, now accepted as the standard Class 1c antidysrhythmic agent according to the current classification

Slow chemistry

The main delaying factor in the flecainide project was simply

Inhibitor of gastric acid secretion. Blocks proton pump

Omeprazole (Losec) MOA

Astra

Omeprazole (Losec) was developed by the company

Peptic ulcer

Omeprazole (Losec) indication

1966

Omeprazole (Losec) project started in

1978 (12 years from when the project started)

Omeprazole (Losec)’s compound was synthesized and its structure determined in

1981 (15 years)

Omeprazole (Losec) phase 1 started in

1988 (22 years)

Omeprazole (Losec) was registered in

Omeprazole (Losec)

Developed by Astra and was the first proton pump inhibitor, and transformed the treatment of peptic ulcers when it was launched in 1988, quickly becoming the company’s best selling drug

carbamates

Astra started a project aimed at developing inhibitors of gastric acid secretion. They started a chemistry programme based on ___, and collaborated with an academic group to develop a suitable in vivo screening assay in rats

• Compounds with weak activity were identified

• Hepatotoxicity problems

In developing inhibitors of gastric acid secretion using carbamates, Astra encountered issues while doing so

Smith, Kline, and French

Developed histamine H2 anatagonists to inhibit gastric acid secretion

benzimidazoles

Searle reported a new class of gastric acid inhibitory compounds ____ which were active but toxic

picoprazole

The forrerunner of omeprazole synthesized in 1976

picoprazole

Was tested in human patients suffering from Zolinger-Ellison syndrome and was found tobe highly effective in reducing acid secretion

omeprazole

An analogue of picoprazole, was synthesized in 1979, and was chosen for development instead of picoprazole

• Poor stability

• Sensitivity to light

The chemical development of omeprazole was complicated by the compound’s

1981

Phase II/III clinical trials of omeprazole began in __, but were halted for 2 years as a result of yet another toxicology scare - carcinogenicity

Inhibits Abl kinase

Imatinib (Gleevec/Glivec) MOA

Novartis

Imatinib (Gleevec/Glivec) was developed by the company

Chronic myeloid leukemia

Imatinib (Gleevec/Glivec) indication

1983

Imatinib (Gleevec/Glivec) project started in

1990 (7 years)

Imatinib (Gleevec/Glivec)’s compound was synthesized or its structure determined in

2001 (18 years)

Imatinib (Gleevec/Glivec) was registered in

Chronic myeloid leukemia (CML)

In the mid-1980s, it was discovered that a rare form of cancer ____, was almost invariably associated with the expression of a specific oncogene product Bcr-Abl kinase. The enhanced tyrosine kinsase activity of this mutated protein was shown to underlie the malignant transformation of the white blood cells

Ciba-Geigy

This oncology team began a project seeking inhibitors of Abl kinase

2-phenylaminopyramidine class

Compounds of the ____ showed selectivity in blocking Abl and PDGF-receptor kinases, and systematic chemical derivatization led to the synthesis of imatinib in 1992, roughly 8 years after starting the project

Imatinib

Proved to have no major shortcomings in relation to pharmacokinetics or toxicology, and was highly effective in suppressing the growth of cells engineered to express Bcr-Abl, and of human tumour cells transplanted into mice. It also inhibited the growth in culture of peripheral blood or bone marrow cells from CML patients

May 2001

Specifically, the imatinib was registered in ___ just 3 years after being tested for the first time in humans

imatinib

Is the first designer kinase inhibitor to be registered (other drugs, such as rapamycin, probably act by kinase inhibition, but this was not known at the time)

imatinib

Has proved efficacious also in certain gastrointestinal tumours, and is the first of a number of kinase inhibitors now used for treating cancer