Fix the mistake: The World Opened Up by Chemistry

The Chemistry of Pharmaceuticals

Pharmaceuticals are a field in which chemical knowledge has been most clearly transformed into human welfare. This lesson surveys the history of drug discovery and modern drug-discovery strategies.

Basic Knowledge

Historical milestones in pharmaceuticals:
・1804: Sertürner isolated morphine from opium (the first pure drug)
・1899: Bayer launched aspirin (acetylsalicylic acid)
・1928: Fleming discovered penicillin, which was put into practical use in 1942 (the antibiotic revolution)
・1932: Domagk discovered sulfonamides (Prontosil)
・1953: Discovery of the DNA double helix → the path to molecular-biological medicines
・1982: Recombinant production of human insulin → the era of biopharmaceuticals
・1986: The first monoclonal antibody drug (muromonab)
・2021: Practical use of mRNA vaccines (COVID-19)

Mechanisms of drug action:
・Enzyme inhibition: aspirin (COX inhibition), statins (HMG-CoA reductase inhibition, lowering cholesterol)
・Receptor agonism/antagonism: adrenergic agonists, beta blockers, antihistamines
・Ion-channel regulation: local anesthetics, antiepileptic drugs
・Transporter inhibition: SSRIs (antidepressants, inhibiting serotonin reuptake), SGLT2 inhibitors (diabetes)
・Inhibition of nucleic acid synthesis: anticancer drugs, antiviral drugs
・Antibody binding: antibody drugs, CAR-T

Drug-discovery process (10–15 years, on the scale of hundreds of billions of yen):
① Target selection → ② Compound screening → ③ Lead optimization → ④ Preclinical studies (animal testing) → ⑤ Phase I/II/III clinical trials → ⑥ Approval (FDA/EMA/PMDA) → ⑦ Phase IV post-marketing surveillance.

Important Terms
Aspirin (COX inhibition, anti-inflammatory and analgesic effects + antiplatelet action; one of the world’s most widely used drugs)
Penicillin (a beta-lactam antibiotic; the 20th-century revolution against infectious diseases)
Pharmacokinetics (ADME) (absorption, distribution, metabolism, and excretion; the movement of a drug through the body)
Prodrug (activated by metabolism in the body; improves absorption or stability)
Bioavailability (the proportion reaching systemic circulation after oral absorption)
Drug interaction (competition between CYP enzymes; caution is needed with combined use)

Further Study (Principles and Applications)

Stereochemistry of drugs: Since the thalidomide incident, the general principle has been to approve only one enantiomer of a drug.
Example: ibuprofen (an anti-inflammatory analgesic) is a racemate, but it is acceptable to use both forms because the R form is isomerized into the S form (epimerization) in the body.
Example: citalopram (an antidepressant) is a racemate, but only the S form was approved as escitalopram at a higher dose and with greater selectivity.
Example: Tamiflu (oseltamivir phosphate) has three asymmetric centers, and only one of its four stereoisomers is active.
Antiviral drugs: They attracted great attention during the COVID-19 pandemic. Remdesivir (an RNA-dependent RNA polymerase inhibitor), molnupiravir (induces mutations in viral RNA), and Paxlovid (a protease inhibitor used with ritonavir).
Cancer immunotherapy: The discovery of the PD-1/PD-L1 pathway, for which Tasuku Honjo received the 2018 Nobel Prize, led to immune checkpoint inhibitors such as Opdivo (nivolumab) and Keytruda. This is a new paradigm in which the immune system is activated to attack tumors rather than attacking tumors directly.
Toxicological perspective (CEO focus): “All substances are poisons; it is the dose that distinguishes a poison from a medicine” (Paracelsus). Even acetaminophen can cause liver necrosis in overdose (>7.5 g), griseofulvin can cause liver damage with long-term use, and the anticoagulant warfarin carries a bleeding risk because it antagonizes vitamin K. Dosage, blood-concentration monitoring, and pharmacokinetics are at the core of modern pharmacy.

Key Points
  • Aspirin, penicillin, and mRNA vaccines mark important turning points in history.
  • Mechanisms of action include enzyme inhibition, receptors, channels, nucleic acid synthesis, and antibodies.
  • Drug discovery takes 10–15 years and hundreds of billions of yen.
  • Stereoisomers can have completely different drug effects (the thalidomide incident).
  • Immune checkpoint inhibition is a new paradigm in cancer treatment.
  • Paracelsus taught that “the dose determines whether something is a poison or a medicine.”
  • Understanding ADME pharmacokinetics is central to modern pharmacy.

Points to Note (Common Confusions and Frequent Mistakes)

① Antibiotics and antiviral drugs are different (antibiotics act only on bacteria and are ineffective against viruses). ② Difference between racemic drugs and single-enantiomer drugs (the latter may reduce side effects and improve efficacy). ③ Vaccines and therapeutic drugs: vaccines prevent disease by providing immunity, whereas therapeutic drugs treat infection after it occurs. ④ OTC drugs and ethical drugs: over-the-counter drugs (no prescription required) and prescription drugs (a prescription is required).

Practice

  1. Explain the mechanism of action of aspirin as inhibition of COX (cyclooxygenase).
  2. State the difference between antibiotics and antiviral drugs and give one representative example of each.
  3. Describe the impact of the thalidomide incident on the stereochemistry of pharmaceuticals.

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