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MedChem Final > Thatcher - Serendipity & Chirality > Flashcards

Thatcher - Serendipity & Chirality Flashcards

1
Q

Phocomelia

A
  • Caused by Thalidomide
    • Drug thought to be safe for morning sickness during pregnancy
  • Thomas Quasthoff
    • German musician with phocomelia
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2
Q

Thalidomide History

A
  • German company - Grunenthal in 1954
  • Serendipitous Finding
    • as an antiemetic –> morning sickness
    • Marketed for insomnia/cold/cough/headaches
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3
Q

Frances Oldham Kelsey

A
  • Richard Merrel demanded Thalidomide FDA approval 6 times
  • Frances DECLINED 6 times
    • due to lack of trial data in the USA
      • Only 17 children w/ thalidomide induced malformations
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4
Q

Enantiomers of Thalidomide

A
  • R-Enantiomer was thought to be safe
    • but was not exactly true –> can interconvert
      • ​DOSE DID NOT MATCH CONC IN HUMANS
        • was not seen in animals
      • higher doses for humans –> led to chiral inversions
  • S-enantiomer
    • ​exerts embryotoxic / teratogenic effect
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5
Q

Uses of Thalidomide

A
  • ENL (Erythema nodosum leprosum) - leprasy form
    • effective @ improving lesions/fevers/night sweats in patients w/ ENL
  • ​MULTIPLE MYELOMA
    • 1999 found to be effective for advanced/refractory MM
    • Outweighs risk of birth defects
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6
Q

Thalidomide MOA

A
  • Anti-Inflammatory
    • INHIBITS TNF-alpha
      • monocyte derived
  • Anti-Agiogenic
    • inhibits angiogenesis
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7
Q

Pomalidomide -> Lenalidomide

A

Druges DERIVED from Pthalidmide

  • Used for:
    • Antiangiogenic
    • Immunomodulatory
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8
Q

Apremilast

A

Drug Derived From Pthalimide

Psoriasis

PDE4 inhibitor

Lower TNF-a (antiinflammatory

Immunomodulatory

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9
Q

Cereblon

A

Component of the E3 Ubiquitine Ligase (pVHL)

of Thalidomide

  • Thalidomide binds to Cereblon
    • –> Promotes recruitment of IKZF1 + IKZF3 (ikaros/aiolos)
      • –> Substrate ubiquination / degradation
  • ​​Thought to be the MoA that causes birth defects!
    • ​downregulating cereblon in chicks/fish
      • –> defects in embryos
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10
Q

Thalidomide as a Cancer Agent

A
  • Downregulator/degrader & Protac
    • ​like SERDS (inhibit and degrade estrogen receptors)
  • Cerebolon = ubiquitine ligase
    • where pthalimide binds
  • LInked with BET ( epigenetic regulator)
    • ​–> ubiquinates target protein
      • –> tells protease to DEGRADE the protein
    • basis to tag proteins to degrade them
    • why its a target for cancer
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11
Q

Serendipitious Discovery

of Omeprazole

Timoprazole

A
  • Start AT CMN131
    • an antisecretory compound
      • but caused liver toxicity (thioamide group)
  • ​​Added analogs
    • ​–> viewed phenotypic Effects
    • Found Timoprazole
      • had anti-secretary affects
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12
Q

​Serendipitious Discovery

Omeprazole

A
  • From Timoprazole
    • we wanted to make it more Anti-Acid
      • ​–> MAKE MORE BASIC
    • ​maximize accumulation of drug within parietal cell
  • ​​Added substituants that make the pyridine MOST BASIC
    • –> increase the pKA
      • Discovered Omerprazole
        • increased thepKa of the pyridine by the most
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13
Q

Unexpected Mechanism

“rational drug design”

of OMEPRAZOLE

A
  • Omeprazole acts on PPI
    • undergoes a BIOACTIVATION process
      • sometimes condisdered a prodrug
    • Reaarangement generates an ELECTROPHILE
      • that reacts with a CYSTEINE in the enzymes
        • the proton pump
      • DISULFIDE FORMATION
        • ​not irreversible but is slow
        • covalent modification of protein target
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14
Q

Omeprazole

Mechanism of Action

A
  • binds to CYS813 / CYS822 on the PPI pump enzyme
    • ATP dependent, sits on membrane
    • Helps maintain acidity in the stomach
  • Target is the Cysteine
    • most NUCLEOPHILIC functional group
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15
Q

Omeprazole

Chirality

A

Omeprazole is a Racemate

  • Sulfur = Chiral Center
  • S-enantiomer was claimed to have better Bioavailability & onset of action​
    • ​True but the S version didnt prove to actually be better than omeprazole.
    • The bioavailability & action was already enough to work
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16
Q

Omeprazole Vs Esomeprazole

A
  • S-Enantiomer did have more BV & onset of action
    • ​BUT NO STATISTICAL DIFFERENCE IN ITS PHYSIOLOGICAL ACTION
      • ​of healing erosive esophagus
  • Faster relief was shown in esopmeprazole
    • but after 1 week symptom relief was the same
  • Unfair Dose Comparison in statistics
    • No signficant difference in its effect vs Omeprazole
17
Q

Studies Between

PPIs for GERD & Ulcer Disease

A

Concluded that there is a

VERY LITTLE DIFFRENCE

in effectiveness of the PPI’s

But a BIG PRICE Difference

MedChem Final (8 decks)

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