Insight into the Pharmaceutical Industry How are drugs discovered and developed?

Global Pharmaceuticals

Areas of focus

The process R&D c20% Marketing/Sales c30%

Patenting Patents protect drugs from copycat versions for 20 years after the drug is invented. This is a bitter pill for pharmaceutical companies because it can take eight years or more after invention to accumulate enough data to get a drug past the U.S. Food and Drug Administration.

Choosing a Disease

Identifying a Drug Target Drug Target = specific macromolecule, or biological system, which the drug will interact with Sometimes this can happen through incidental observation…

Finding the Lead Compound Screening Natural Products Screening synthetic banks “Lead compound” = structure that has some activity against the chosen target, but not yet good enough to be the drug itself. If not known, determine the structure of the “lead compound”

Structure-Activity-Relationships (SAR’s) Which structural features are responsible for its biological activity (i.e. to identify the“pharmacophore”) Pharmacophore = the structural features directly responsible for activity Optimize structure to improve interactions with target

Computer aided drug design If one knows the precise molecular structure of the target (enzyme or receptor), then one can use a computer to design a perfectly-fitting ligand. Drawbacks: Most commercially available programs do not allow conformational movement in the target (as the ligand is being designed and/or docked into the active site). Thus, most programs are somewhat inaccurate representations of reality.

Choosing the Bioassay bioassay = A test used to determine biological activity In vitro: In an artificial environment, as in a test tube or culture media In vivo: In the living body, referring to tests conducted in living animals.

Toxicity Toxicity standards are continually becoming tougher Must use in vivo (i.e. animal) testing to screen for toxicity Each animal is slightly different, with different metabolic systems, etc. Thus a drug may be toxic to one species and not to another

Metabolism of Drugs The body regards drugs as foreign substances, not produced naturally. Sometimes such substances are referred to as “xenobiotics” Body has “goal” of removing such xenobiotics from system by excretion in the urine The kidney is set up to allow polar substances to escape in the urine, so the body tries to chemically transform the drugs into more polar structures.

PKPD Pharmacodynamics explores what a drug does to the body, whereas pharmacokinetics explores what the body does to the drug.

ADME ADME stands for absorption, distribution, metabolism, and excretion

Manufacture of Drugs Pharmaceutical companies must make a profit to continue to exist Therefore, drugs must be sold at a profit One must have readily available, inexpensive starting materials One must have an efficient synthetic route to the compound As few steps as possible Inexpensive reagents

The route must be suitable to the “scale up” needed for the production of at least tens of kilograms of final product This may limit the structural complexity and/or ultimate size (i.e. mw) of the final product In some cases, it may be useful to design microbial processes which produce highly functional, advanced intermediates. This type of process usually is more efficient than trying to prepare the same intermediate using synthetic methodology.

Clinical Trials Pre-clinical: animals Phase I: Drug is tested on healthy volunteers to determine toxicity relative to dose and to screen for unexpected side effects Phase II: Drug is tested on small group of patients to see if drug has any beneficial effect and to determine the dose level needed for this effect Phase III: Drug is tested on much larger group of patients and compared with existing treatments and with a placebo

FDA approval

Post patent expiration Generic drugs are copies of brand-name drugs that have exactly the same dosage, intended use, effects, side effects, route of administration, risks, safety, and strength as the original drug. In other words, their pharmacological effects are exactly the same as those of their brand-name counterparts