The Discovery of Vorapaxar (SCH 530348), a Thrombin Receptor (Protease Activated Receptor-1) Antagonist with Potent Antiplatelet Effects - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 37

X

H

X

H H

O

9 3

O

3a
4

3

R 2

H H

R 2

H H

R 1

R 1

2

′

2 ′

N

N

6 ′

R 3

5 ′

R 4

Structure type B

Structure type A

.

PAR-1 IC 50
(nM)

Rat oral
absorption No. Str. type X R 1 R 2 R 3 R 4

( )-9 A O Me H Me H 300 nM low

( þ )-10a A O Me H Me H 150 low

( þ )-22 A O Me H Et H 20 low

ND a ( )-23 A O Me H H Me 1100

( )-24 A O Me H Ph H 410 000 ND

( þ )-25 A O Me H H Ph 27 high

( )-26 A H, OH Me H Et H 3500 ND

( )-27 A H, H Me H fused phenyl (quinolyl) 8000 ND

( )-28 B O Me H quinolyl 150 low

( )-29 B O H H quinolyl 200 ND

( )-30 B O Me Me quinolyl 150 ND

( )-31 B O Et H quinolyl 1500 ND

a ND ¼ not determined.