MedChem

What are the differences between IFN-1a and IFN 1b?

• IFN-1a

  • glycosylated at Asn 80→ more stable in body and longer half-life

  • 166 amino acids

• IFN-1b

  • nonglycosylated

  • 165 amino acids

• similarities

  • disulphide bridge Cys 31-141

  • highly polar, so mostly in periphery

What is glatiramer acetate?

• synthetic polypeptide

  • Alanine, glutamate, lysine and tyrosine 

• acts in periphery 

• cannot give orally → amide bonds undergo degradation in the gut 

Teriflunomide

How does teriflunomide work? 

• is active metabolite of leflunomide (prodrug) used in RA

  • had isoxazole ring that undergoes degradation by 1A2

• in MS use just the active metabolite 

  • triflouro increases lipophilicity → act in CNS and periphery 

Cladribine

How does cladribine work?

• pharmacophore: Purine + pentose (5 member sugar) 

• Cl @C2 → stable for oral route 

  • w/o or change to amine or alkyl group lose that 

  • could change to Br 

• prodrug → cladribine triphosphate 

  • via deoxycytidine kinase adds 3 phosphate groups (in periphery or CNS) 

Dimethyl fumarate

How does dimethyl fumarate work?

• consider prodrug (parent some activity) → monomethyl fumarate

  • when only 1 ester undergoes hydrolysis 

• needs to be an unsaturated ester with trans geometry 

  • double bond = light sensitive 

Why can dimethyl fumarate not be combined with alcohol?

• ester can under degradation and become ethylester (Me → Et) 

  • activity decreases 

Fingolimod

How does fingolimod work?

• amino alcohol derivative 

• amphiphilic molecule → good into CNS

  • long lipophilic tail 

  • propene dialcohol polar head 

• very potent > affinity vs natural substrate 

• prodrug → fingolimod-phosphate

  • attaches monophosphate by sphingosine kinase

Ozanimod

How does ozanimod work?

• pharmacophore: indane +oxadiazole 

• amphiphilic molecule → good into CNS

  • aminoethanol polar group

  • ethoepxy phenol lipophilic group 

• more potent than fingolimod 

  • less cytotoxic profile b/c more selective to receptor 

• active metabolites + active parent

What are the ozanimod metabolites?

*metabolites from rapid first pass effect by 3A4 and other alcohol related enzymes 

• M1 → alcohol convert to acid 

• M2 → alcohol degraded to primary amine 

• M3 → alcohol converted to methyl ketone

Ponesimod

How does ponesimod work?

• pharmacophore: thiazolidine

• amphiphilic molecule → good into CNS

  • polar alcohol functional groups

  • 2 lipophilic groups - aminopropyl and methylbenzene

• more potent than fingolimod, and less potent than ozanimod