Most Important Drugs in History

Salvarson

first modern chemotherapeutic agent

• treats syphilis

• discovered by Paul Ehrlich in 1910

Salvarson structure

Salvarson mechansim

little known about mode of action

assumed to affect a target present in the pathogen

Penicillins

generic name for class of antibiotics

• 1928 Alexander Fleming

• accidental discovery mold growing on culture of Staphylococcus aureus (drug produced from mold)

• replicated and produced by Howard Florey in 1940 (WWII)

• Ersnt Boris Chain

Penicillin core structure

R is a variable group

Penicillin mechanism

actively kills bacteria by stopping them from building a strong cell wall

6-Mercapto-Purine

• 1953 first FDA approved drug synthesized by rational design

• treats childhood leukemia, used for organ transplants

• Gertrude Elion and George Hitchings

6-MP structure

6-MP mechanism

interfers with nucleic acid synthesis and purine metabolism, slows growth of dividing cancer cells and immune cells

Thalidomide

• sedative

• based on barbiturate structure (CNS depressants)

• racemate (50/50 mix of stereoisomer) — only R-thalidomide is safe

• S-thalidomide causes birth defects

  • synthesized by Swiss company in 1950s

Thalidomide structure

Thalidomide mechanism

potentiates GABA (primary neurotransmitter in CNS), binds to alpha subunit

Azidothymidine (AZT)

• HIV/AIDS treatment

• 1964 Horwitz synthesized AZT

• 1974 Ostertag found that it inhibits replication of leukemia-causing retrovirus

• 1983 discovered retrovirus may affect AIDS patients

• 1987 AZT approved by FDA

AZT structure

AZ

AZT mechanism

inhibits reverse transcriptase that HIV uses to synthesize DNA, preventing viral formation

nucleoside analog (pretends to be a nucleoside and inserted into new DNA, terminating chain)

Hydrocortisone

cortisol when used as a medication

• treats inflammation and autoimmune conditions

• 1948-49 found to treat rheumatoid arthritis

• Edward Kendall, Tadeus Reichstein, Philip Hench

Hydrocortisone structure

general tetracyclic structure

Hydrocortisone mechanism

cortisol is a glucocorticoid (steroid hormones that regulate glucose metabolism), binds to GC receptor part of feedback mechanism in immune system which reduces inflammation

Thorazine

• treats schizophrenia, mania, and other psycotic disorders

• 1950 Phone-Poulenc

• 1954 thorazine used in USA

Thorazine structure

Thorazine mechanism

blocks dopamine D2 receptors, diminishing neurotransmitter binding which causes more dopamine release

Librium

• first benzodiazepine synthesized

• amnestic, anticonvulsant, hypnotic, and skeletal muscle relaxant properties

• 1957 Sternbach

• 1958 FDA approved

• further developed into valium

• addictive

Librium structure

Librium mechanism

enhances the effect of GABA at GABAa receptor

Ivermectin

• treats river blindness (congo basin caused by parasite)

• 1974 research started based on soil-dwelling Streptomyces avermectinius (antiparisitic)

• Satoshi Omura

Ivermectin structure

b form more powerful

Ivermectin mechanism

binds selectively/with high affinity to glutamate-gated chloride channels in nerve/muscle cells of invertebrate→ increased permeability of the cell membrane to chlorine ions resulting in the death of parasite

has low affinity for mammalian ligand channels

ciclosporin (CsA)

• immunosuppressant used in organ transplantation

• isolated from fungus in soil sample from Norway in 1969

  • first metabolite from microorganism used to regulate mammalian cells

ciclosporin structure

ciclosporin mechanism

enters cell → binds with cyclophilin protein → this complex inhibits the cytoplasmic phosphatase Calcineurin → blocks T cell activation