B. Springthorpe et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6013–6018
6017
NH2.HCl
(f) identifying metabolically stable neutral compounds
by modifying the hydrophobic phenylcyclopropyl
group and the hydroxylic side chain substituent.
HO
OAc
N(BOC)2
HO
HO
a
b, c
HO
OH
24
25
26
In making these changes, the structure–activity relation-
ships moved away from dependency on the acidic side
chain, allowing identification of potent and orally bio-
available non-nucleotide reversible P2Y12 antagonists.
Compound 17 has now progressed to phase III clinical
trials in acute coronary syndromes.
HO
NHCbz
HO
NH2
O
d, e
f, g, h
i
O
O
O
O
27
28
Cl
N
Cl
N
N
N
N
H2N
HN
N
N
HO
Acknowledgments
HO
O
S
O
O
S
j
We thank Jim Murray, Dawn Adkin and Kate Harris
for formulation support. We also thank Iain Beattie,
Michael Bernstein, Kim Lawson, Hemlata Pancholi
and Andy Wright for analytical support.
O
O
O
30
29
F
F
Supplementary data
HN
N
k, l
N
N
Experimental details for the General Schemes 1 and 2
and supporting analytical data (NMR, MS and elemen-
tal analyses) for compounds 2–18 can be found in the
online version. Supplementary data associated with this
article can be found, in the online version, at
N
HO
N
O
S
HO
OH
17
Scheme 3b. Reagents and conditions: (a) (BOC)2NNa, Pd(PPh3)4,
THF (92%); (b) OsO4, NMO, THF, H2O (100%); (c) HCl, MeOH,
H2O (96%); (d) dimethoxypropane, pTSA, acetone (86%); (e) CbzCl,
DIPEA, MIBK (95%); (f) ButOK, ethyl bromoacetate, THF;
(g) LiBH4, THF (86%; two steps); (h) H2, Pd/C, EtOH (99%);
(i) 4,6-dichloro-2-propylthio-pyrimidine-5-amine, DIPEA, DMF
(75%); (j) isoamylnitrite, CH3CN (88%); (k) 23, DIPEA, DCM
(99%); (l) TFA, H2O (90%).
References and notes
1. Frishman, W. H.; Burns, B.; Atac, B.; Alturak, N.;
Altajar, B.; Lerrick, K. Am. Heart J. 1995, 130, 877.
2. Leff, P.; Robertson, M. J.; Humphries, R. G. In Purinergic
Approaches in Experimental Therapeutics; Jacobson, K.
A., Jarvis, M. J., Eds.; Wiley-Liss: New York, 1997; pp
203–216.
3. (a) CAPRIE Steering Committee (CAPRIE). Lancet 1996,
348, 1329; (b) The Clopidogrel in Unstable Angina to
Prevent Recurrent Events Trial Investigators (CURE).
N. Engl. J. Med. 2001, 345, 494.
chloro displacement with amine 23 followed by depro-
tection gives 17.
4. (a) Ingall, A. H.; Dixon, J.; Bailey, A.; Coombs, M. E.; Cox,
D.; McInally, J. I.; Hunt, S. F.; Kindon, N. D.; Teobald, B.
J.; Willis, P. A.; Humphries, R. G.; Leff, P.; Clegg, J. A.;
Smith, J. A.;Tomlinson, W. J. Med. Chem. 1999, 42, 213; (b)
Humphries, R. G. Haematologica 2000, 85, 66.
5. Albert, A.. In Advances in Heterocyclic Chemistry; Katri-
tzky, A. R., Ed.; Academic Press, 1986; 39, pp 117–180.
6. Marquez, V. E.; Lim, M. L. Med. Res. Rev. 1986, 6, 1.
7. Aggregation of human washed platelets was assessed
turbidimetrically in 96-well plates as a decrease in absor-
bance (650 nm). The washed platelets were incubated with
the test compounds for 5 min before addition of 30 lM
ADP. Antagonist potency was estimated as a % inhibition
of the control ADP response to obtain a pIC50. Full assay
details are given in: Humphries, R. G.; Tomlinson, W.;
Ingall, A. H.; Cage, P. A.; Leff, P. Br. J. Pharmacol. 1994,
113, 1057.
Phase I and phase II studies have confirmed the pre-
dicted pharmacokinetic and pharmacodynamic profile
of the compound and a double blind comparison with
clopidogrel, on a background of low-dose aspirin, has
shown 17 to have superior anti-platelet activity as mea-
sured ex vivo by light transmission aggregometry.18
In summary, beginning with ATP, a poor lead for an
oral programme, we have discovered oral P2Y12 antag-
onists with clinical potential. Key elements in the medic-
inal chemical journey from ATP to 1 to 17 were:
(a) introducing affinity-enhancing 5,7-hydrophobic
substituents;
(b) replacement of the labile triphosphate group;
(c) changing the core purine to a triazolopyrimidine,
increasing affinity >100-fold;
(d) finding the first nonacidic reversible antagonists
(e.g., 6 and 7);
(e) introducing the trans-2-phenylcyclopropylamino
substituent, increasing affinity >10-fold; and
8. Binding data were obtained in washed platelets in 96-well
plates, each well containing [125I] radiolabelled P2Y12
antagonist, test compounds and washed platelets. After
30 min incubation, the reaction was terminated by filtra-
tion, washing of the platelets and the bound radioactivity
was measured and used to derive a pKi. Full assay details