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 38

2.4.4.1.2 First-generation Thrombin Receptor Antagonists. The C 6 0 -ethyl-
pyridine derivative 22 was the first benchmark compound which showed a
promising spectrum of activity in the binding assay, functional assays, and a
monkey ex vivo platelet aggregation assay (Figure 2.7). It showed a K i value
of 12 nM against PAR-1 in the binding assay, and it inhibited aggregation of
washed human platelets induced by TRAP with an IC 50 of 70 nM. In a cyno-
molgus monkey ex vivo platelet aggregation model, compound 22 caused
complete inhibition of TRAP-induced platelet aggregation at 10mg kg 1
upon intravenous administration (over 30min).
However, compound 22 showed poor oral bioavailability (F ¼ 3% in rat).
Our efforts to identify compounds with good oral bioavailability led to C 5 0 -aryl
derivatives (e.g., 25), which, in general, showed good potency and oral bioa-
vailability. The synthesis of C 5 0 -aryl derivatives was carried out by Suzuki
reaction of the corresponding triflate or bromide (Scheme 2.2). 59 From this sub-
series, compound 33 was identified as our first recommended candidate for
development (Table 2.4).
The C 5 0 -aryl derivative 33 was a competitive antagonist of PAR-1 with a K i
value of 2.7 nM in the binding assay. It showed robust inhibition of thrombin-
induced platelet aggregation and TRAP-induced platelet aggregation (IC 50
values of 44 and 24 nM, respectively), whereas it showed no inhibition of ADP-
and collagen-induced aggregation of platelets, thereby demonstrating the spe-
cificity of the compound within the platelet activation mechanism. 21 In a
thrombin-induced calcium transient assay 32 in human coronary artery smooth
muscle cells (HCASM), this compound showed a K d value of 2.6 nM. The
compound inhibited thrombin-induced thymidine incorporation 32 in HCASM
with a K i of 13.0 nM. In rat, compound 33 showed an oral bioavailability of

O

H H

O

H H

Me

N

Et

22

PAR-1 Ki = 20 nM 59
Inhibition of human
platelet aggregation, IC 50 = 70 nM

Figure 2.7 An early benchmark PAR-1 antagonist, himbacine derivative 22 showed
potent PAR-1 inhibition in the binding assay and in functional assays. It
also showed complete inhibition of TRAP-induced platelet aggregation in
an ex vivo assay in cynomolgus monkeys following intravenous admin-
istration (10mg kg 1 , infusion over 30min).