31 - MS Medchem

Question 1

Which MS drug?

blocks lymphocyte EGRESS

reduces the lymphocytes –> CNS

Answer 1

FINGOLIMOD

Question 2

Which MS drug?

depletes Lymphocytes Peripherally
VVV
reduces lymphocytes in CNS

Answer 2

CLADRIBINE

Question 3

Which MS drug?

prevents lymphocyte ADHESION

Answer 3

NATALIZUMAB
NAT-HESION

Question 4

How was ISP-1 (myriocin)
OPTIMIZED to become FINGOLIMOD?

Answer 4

1) Elimination of Chiral Centers
2) Removal of Side Chain Fxns

3) Vary Chain Length
* *24f (15) = MORE TOXIC >** 24e (14) alkyl side chains

4) Incorporation of PHENYL RING –> improved ADMET
fascilitate spectrscopic detection

5) VARY CHAIN LENGTH AGAIN!
increased the MST (mean survival time) in mice skin allografts

Question 5

ISP-1 = Myriocin

Answer 5

TOXIC - from FUNGI
mimics a FATTY ACID
poor solubility

Has IMS properties –> inhibitor of Serine Palmitotryansferase

• BUT FTY720 (FINGOLIMOD) is NOT an inhibitor*
• phenotypic based not mechanism based*

Lead Compound for FINGOLIMOD

Question 6

Phenotypic Approach:

Which compound had the greatest MST (mean survival time)
in rat skin allografts?
Fingolimod Discovery

Answer 6

• *24F**
• *15 alkyl side chains**

BUT it was also MORE TOXIC
Compared to 24e (14)

Question 7

What does FINGOLIMOD need to be
functional at SP-receptors?

Answer 7

PHOSPHORYLATION

• *Fingolimod-Phos**
• -> induces internalization of S1P1 subtype of receptors

Fingolimod = Sphingosine Memetic

Question 8

Sphingosine

Answer 8

Sphingosine & Ceramide
are important
Messenger Molecules in Membranes

Question 9

Fingolimod-Phosphate
Is an agonist at WHAT RECEPTORS?

Answer 9

Agonist @ 1345
all except S1P2

• *S1P1**
• *retention of lymphocytes** + disruption of cytoskeleton
• *S1P3**
• bradycardia* + disruption of cytoskeleton
• *S1P5**
• *neurprotection**

Question 10

Fingolimod-Phosphate’s
AGONISM @ S1P1
causes WHAT?

Answer 10

functional ANTAGONISM

S1P1 -> retention of lymphocytes

So agonism causes:
Internalization of Receptor (*down-modulation of S1P1)_
&
_inhibition* of leukocyte egress

Question 11

What are the goals of
NEXT-GEN Fingolimod’?

Answer 11

Greater S1P1 Selectivity > S1P3
S1P3 = bradycardia –> so not targetting = improved cardiac safety

OZANIMOD
10x more S1P1 selectivity

Ponesimod / Siponimod

Question 12

Which MS drug?

Answer 12

• *TERIFLUNOMIDE**
• *active metabolite of LEFLUNOMIDE** (DMARD in RA)
• Inhibits:*
• *Dihydroorotate Dehydrogenase -> de novo PYRIMIDINE synthesis**

Question 13

Which MS drug?

INHIBITS:
DiHydroOrotate Dehydrogenase
VVV
inhibits DE-NOVO PYRIMIDINE synthesis

Answer 13

TERIFLUNOMIDE
active metabolite of leflunomide

does NOT deplete Lymphocytes

• Reduces*
• *TH1 / TH17**

Increases TH2

Interferes with T-Cell activation

Question 14

What type of Drug Discovery was
FINGOLIMOD?

Answer 14

PHENOTYPIC
drug discovery

Driven by:
IMS phenotype –> classical med chem

Question 15

DiMethyl Fumarate

Answer 15

Drug with UNKNOWN MoA

but is still getting FDA funding

Reactive to AA’s in Proteins –> can modify many things
important for biosynthesis

QUnone = electrophile
cause LIVER toxicity