Reversible, orally available ADP receptor (P2Y12) antagonists Part I: Hit to lead process

Article abstract of DOI:10.1016/j.bmcl.2018.03.090

A hit to lead process to identify reversible, orally available ADP receptor (P2Y₁₂) antagonists lead compounds is described. High throughput screening afforded 1. Optimization of 1, using parallel synthesis methods, a methyl scan to identify promising regions for optimization, and exploratory SAR on these regions, provided 22 and 23. Compound 23 is an orally available, competitive reversible antagonist (K_B = 94 nM for inhibition of ADP-induced platelet aggregation). It exhibits high metabolic stability in human, rat and dog liver microsomes and is orally absorbed. Although plasma level after oral dosing of 22 and 23 to rats is low, reasonable levels were achieved to merit extensive lead optimization of this structural class.

Full text of DOI:10.1016/j.bmcl.2018.03.090

Accepted Manuscript
Reversible, Orally Available ADP Receptor (P2Y12) Antagonists Part I: Hit to
Lead Process
Imadul Islam, Shendong Yuan, Robert G. Wei, Wei Xu, Michael Morrissey,
Raju Mohan, Dewan Zheng, Andrea DiMella, Laura Dunning, Michael Snider,
Babu Subramanyam, Jih-Lie Tseng, Judi A. Bryant, Brad O. Buckman
PII:
S0960-894X(18)30295-6
https://doi.org/10.1016/j.bmcl.2018.03.090
BMCL 25744
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 January 2018
26 March 2018
30 March 2018
Please cite this article as: Islam, I., Yuan, S., Wei, R.G., Xu, W., Morrissey, M., Mohan, R., Zheng, D., DiMella,
A., Dunning, L., Snider, M., Subramanyam, B., Tseng, J-L., Bryant, J.A., Buckman, B.O., Reversible, Orally
Available ADP Receptor (P2Y12) Antagonists Part I: Hit to Lead Process, Bioorganic & Medicinal Chemistry
Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.03.090
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Reversible, Orally Available ADP Receptor (P2Y12) Antagonists Part I:
Hit to Lead Process
Imadul Islam,ab* Shendong Yuan,b Robert G. Wei,b Wei Xu,b Michael Morrissey,b Raju Mohan,b
Dewan Zheng,c Andrea DiMella,c Laura Dunning,c Michael Snider,c Babu Subramanyam ,d Jih-
Lie Tseng ,d Judi A. Bryant,b and Brad O. Buckmanb
aMedical Core Facility and Research Platforms, King Abdullah International Medical Research
Center/King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard-
Health Affairs, Riyadh 11426, Saudi Arabia,
c
d
bDepartments of Medicinal Chemistry, Molecular Pharmacology and Pharmacology,Berlex
Biosciences, 2600 Hilltop Drive Richmond, CA 94804
Abstract: A hit to lead process to identify reversible, orally available ADP receptor (P2Y12)
antagonists lead compounds is described. High throughput screening afforded 1. Optimization
of 1, using parallel synthesis methods, a methyl scan to identify promising regions for
optimization, and exploratory SAR on these regions, provided 22 and 23. Compound 23 is an
orally available, competitive reversible antagonist (KB = 94 nM for inhibition of ADP-induced
platelet aggregation). It exhibits high metabolic stability in human, rat and dog liver microsomes
and is orally absorbed. Although plasma level after oral dosing of 22 and 23 to rats is low,
reasonable levels were achieved to merit extensive lead optimization of this structural class.
______________________________________________________________________________
Antiplatelet therapy reduces mortality and non-fatal events in patients with atherothrombotic

disease. Aspirin, which is modestly efficacious and relatively safe, remains the standard
reference compound for antiplatelet treatment.1 Clopidogrel (PlavixTM) is slightly more effective
than aspirin (8.7% added benefit).2 When taken with aspirin, clopidogrel further reduces
coronary events by 19%; however, the combination therapy results in a 30% increase in major
bleeding compared to aspirin treatment alone.3 Besides bleeding complications, there are other
limitations and concerns about clopidogrel’s use. It undergoes hepatic metabolism to produce
active metabolites4,5,6 that irreversibly inhibit the platelet ADP receptor P2Y12.7 At the
therapeutic dose of 75 mg/day, 3 to 5 days are necessary to reach steady state inhibition of
ADP-induced platelet aggregation, with inhibition levels between 40-60%.8 Additionally,
clopidogrel has a slow offset of action (about 5 days)8, and there is a potential for drug
resistance,9,10,11,12, and drug-drug interaction13,14. While the beneficial effects of oral
antiplatelet therapy are well established, the limitations of aspirin and clopidogrel, both
irreversible inhibitors of platelet aggregation, underscore the need for new oral agents with
improved efficacy and safety profiles.15 Cangrelor (approved 2015) and ticagrelor ( approved
2011) are reversible P2Y12 inhibitors which are administered intravenously, thus have
16,17
disadvantage over oral reversible P2Y12 inhibitors.
Therefore, search for new P2Y12
inhibitors having strong inhibition of platelet aggregation and low risk of bleeding are still being
perused.18 To achieve this goal we have already published in vitro effect, pharmacokinetic
characterization and inhibition of platelet aggregation and thrombus formation in rat and dog
model of novel and preclinical P2Y12 antagonists BX 667 and metabolite BX 048.19,20,21 Here in,
we report hit to lead process to discover reversible, orally available ADP receptor (P2Y12)
Antagonists.

Chart 1: HTS and Parallel Synthetic Hits
O
H
N
N
O
N
O
O
1
IC50 = 860 nM
Cmax (2 mpk) = 2700 nM
O
O
H
O
H
N
N
N
N
N
O
N
O
O
N
O
2
3
O
O
IC50 = 690 nM
IC50 = 1800 nM
Cmax (2 mpk) = 1200 nM
F(rat) = 42%
Cmax (2 mpk) = 1500 nM
High Throughput Screening (HTS) of the Berlex proprietary library in a radioligand binding
assay, which measured [33P]2-MeSADP displacement from intact washed human platelets19,
provided the validated hit 1 (Chart 1). Although 1 exhibited sufficient potency and exposure
levels after oral administration to rats to be considered a lead,22 it contained an undesirable
fluorenylmethyl group. The presence of two amide bonds in 1 made it a good candidate for
parallel synthesis methods to find a replacement for the fluorenylmethyl group and to enable
rapid SAR development. Utilizing a fragment of 1, libraries of amides, carbamates, ureas and
sulfonamides were synthesized; in total, 995 library compounds were prepared and tested
(Schemes 1 and 2). Despite the relatively large number of compounds synthesized, only two
library compounds, 2 and 3, had reasonable potency in the binding assay (IC50 < 3000 nM) to
merit further evaluation. Compound 2, with similar potency to 1 and reasonable exposure
levels after oral dosing,22 was selected for further optimization.

Scheme 1.
R6
O
N
O
O
N
O
O
NHBOC
i, ii, iii
H
HO
NH
+
N
R4
37a-o
N
O
N
R4
O
36
Amino Acids: Gly, S-Val, S-Phe,
Asp( OBn) , S-Glu( OBn) ,
S-Lys( 2-chlorobenzyl) , Ser( OBn) ,
S-Asn, S-Gln, S-His, S-Trp, R-
Asp( OBn) , R-Glu( OBn) , S-Homo
Glu( OBn) , Carboxymethyl-S-
cysteine( OMe)
O
2, 13, 20, 21, 23-25, 27-32, 34
22 iv, 26
v
ii
33
35
Reagents and conditions. (i) EDC, HOBt, DIEA, amino acids 37 a-o, CH2Cl2; 67-91% (ii) TFA, CH2Cl2; 95-100% (iii) EDC, HOBt, DIEA,
CH2Cl2/DMF, 4-methoxy-2-carboxyquinoline or 4-hydroxy-2-carboxyquinoline; 70-90% (iv) glycine(OtBu), EDC, HOBt, DIEA, THF; 85% (v)
ethyl bromoacetic acid, KHMDS, THF; 65%
Scheme 2.
O
O
NH2
NHR
N
N
i or ii or iii
O
N
O
N
O
O
38
995 compound library,
including 2 and 3
Reagents and conditions. (i) acid chloride, sulfonyl chloride or carbamoyl chloride, DIEA, DMAC/DME; 80-95% (ii) isocyanates, DIEA,
DMAC;62-70% (iii) carboxylic acids, DIEA, isobutyl chloroformate in THF, DMAC;55-83%
To prioritize areas on 2 to optimize, a “methyl scan” was performed by systematically adding
or deleting a single methyl group at different sites on the molecule (Schemes 1, 3, 4, and 5).
Scheme 3.
OH
N
OR6
N
O
i
O
H
H
N
N
N
N
O
N
O
O
N
O
O
O
13
12, 14, 15
Reagents and conditions. (i) Cs2CO3, DMF; 55-73% ethyliodide for 12, propyliodide for 14, benzylbromide for 15
Scheme 4.
O
N
O
N
i, ii or i, iii or
i, iv or i, v
O
O
H
H
N
N
N
N
N
O
N
O
R1
H
43g
4, 17-19
and 1000 compound library

Reagents and conditions. (i) TFA, CH2Cl2; (ii) Et3N, CH2Cl2methyl chloroforamte2; 64-89% (iii) DIEA, DMAC, isocyanates;56-85% (iii)
DIEA, DMAC, carboxylic acids, isobutyl chloroformate in THF; 70-89%(iv) DIEA, DMAC/DME.acid chlorides, sulfonyl chlorides or
carbamoyl chlorides;67-89%
Scheme 5.
O
N
O
N
O
O
i, ii
R5
N
NHR5
+
HO
EtO
HO
R4
39a R4 = H, R5 = H
39b R4 = H, R5 = Me
39c R4 = R-Me, R5 = H
39d R4 = S-Me, R5 = H
O
O
R4
40a R4 = H, R4 = H
40b R4 = H, R5 = Me
40c R4 = R-Me, R5 = H
40d R4 = S-Me, R5 = H
i
i
i
O
N
5, 6, 9, 10, 11, 16,
43e R= Bn, R2= H, R3= S-Me, R5= H
R5
N
R3
O
iv, v
iv, v
7
R2
R
43f R= Bn, R2= H, R3= R-Me, R5= H
N
8
N
O
43g R= BOC, R2= H, R3= H, R5= H
42a R2 = R-Me, R3 = H, R7 = H, R8 = H
vi, v, iv
42b R2 = R-Me, R3=H, R7 = CO( O) Et, R8 = H
R2
R3
42c R2 = S-Me, R3=H, R7 = CO( O) Et, R8 = Bn
42d R2 = S-Me, R3=H, R7 = CO( O) Et, R8 = H
N
NH
R7
N
N R8
iv
41
42e R2 = H, R3 = S-Me, R7 =Bn, R8 = H
42f R2 = H, R3 = R-Me, R7 = Bn, R8 = H
Reagents and conditions. (i) EDC, HOBt, CH2Cl2, Et3N;65-90% (ii) LIOH, MeOH/H2O;84-90% (iii) EDC, HOBt, CH2Cl2, Et3N;67-90% 36 or
41 or 42b or 42d or 42e of 42f or Boc piperazine (42g); (iv) Pd/C, H2, MeOH; 89% (v) ethyl chloroformate, Et3N, CH2Cl2;82% (vi) benzyl
chloride, Et3N, CH2Cl2 0 °C; 67%
Data from the “methyl scan” are presented in Table 1 and a representation of methyl group
tolerance is shown in Chart 2. Incorporation of a methyl group throughout the molecule is
generally tolerated (5 - 9, 12), with the exception of replacing glycine with either D-alanine (10)
or N-methyl glycine (11). However, the removal of a methyl group at two different sites (4 and
13) was not tolerated. Based on these methyl scan data (Table 1) and an analysis of the
synthetic complexity for making additional analogs at each sites, three areas were prioritized

for initial optimization efforts: 1) phenol analogs, 2) ethyl carbamate analogs, 3) amino acid
scan at the glycine site (Chart 2).
Chart 2. Areas Tolerant of Methyl Group Substitution.
O
O
H
N
N
N
O
O
N
O
Table 1. Methyl Scan assay results for compounds 4-13
R6
O
R3
O
R5
N
R2
O
N
N
O
N
R4
O
R1
Cmpd
R1
R2
R3
R4
R5
R6
IC50
(nM)a
2
4
5
6
7
8
9
10
11
12
13
Et
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
H
H
S-Me
R-Me
H
H
H
H
H
H
H
H
H
R-Me
S-Me
H
H
H
H
H
H
H
H
H
H
S-Me
R-Me
H
H
H
H
H
H
H
H
H
Me 690
Me >3000b
Me 1700
Me 4300
Me 4500
Me 1100
Me 1900
Me 14000
Me Me 21000
H
H
H
H
H
H
Et
840
H
H
>2000b
aValues represent the average of at least two experiments. bHighest concentration tested.
Alkylation of the phenolic oxygen of 13 provided a simple means to generate exploratory SAR
at this site (Scheme 3). Although only a small number of phenolic ether analogs were
synthesized, small alkyl ethers, 2, 12, 14, are preferred over the larger benzyl ether analog 15.
Ethyl carbamate analogs were synthesized from carboxylic acid 40a (Scheme 5) or through
parallel synthesis methods on amine 43g (Scheme 4). Of the 1000 library analogs synthesized,
few active compounds were identified (examples include 16–19), and none were more potent
than 2 (Table 2). Conversely, an amino acid scan at the glycine site of 2, employing naturally
occurring amino acids (Scheme 1), provided a range of acceptable functionality: alkyl, 9 and 20;
amides, 26 and 27; alcohol, 25; imidazole, 28; and carboxylic acids, 22 and 23, but the lysine

analog 24 and the aromatic amino acids, 21 and 29, were not tolerated (Tables 1 and 2). There
was a clear preference for carboxylic acid-containing amino acids, suggesting that this could be
a fruitful area for optimization. To further explore SAR at this site a number of acid-containing
unnatural amino acids were incorporated into 2 (Scheme 1 and 5). Several analogs had
reasonable potency, three of which gave IC50 values less than 500 nM, 32, 34, 35. In addition, S-
amino acids 22 and 23 are preferred over the corresponding R-amino acids 30 and 31. With
some SAR established for this potential lead series, and a 6-fold increase in potency for 23 over
the high throughput screening lead 1, compound 23 was selected for further characterization.
Pharmacological characterization of 23 was carried out by the method of Schild23.
Concentration-response curves of 23 on ADP-induced platelet aggregation in the absence and
presence of three increasing concentrations of 23 is shown in Figure 1. From these data a
reciprocal replot was constructed, which quantitatively resulted in a slope of 0.82 and KB = 94
nM. The pharmacologic behavior of 23 is consistent with a competitive, reversible mechanism
of action as indicated by the parallel shift to the right in the concentration-response curves with
negligible attenuation of the maximal response.
Figure 1. Concentration response curve of 23 on ADP-induced platelet aggregation

Table 2. ADP Receptor Binding Activity
R6
O
N
O
H
N
N
N
R4
O
R1
Cmpd R1
R4
R6
IC50
(nM)a
2
CO2Et
CO2Et
CO2Et
(3-Me)Ph
CONHtBu
CO(CH2)4CH3
CO(4-Et)Ph
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
H
H
H
H
H
H
Me 690
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
Pr
Bn
520
>3000b
Me 890
Me 910
Me 1200
Me 1800
Me 1500
Me 8600
Me 150
Me 86
Me 26000
Me 1100
Me 2100
Me 2500
S-iPr
S-Bn
S-CH2CO2H
S-(CH2)2CO2H
S-(CH2)4NH2
S-CH2OH
S-CH2CONH2
S-(CH2)2CONH2
S-CH2(3H-imidazol-4yl) Me 1500
S-CH2(1H-indol-3-yl)
R-CH2CO2H
R-(CH2)2CO2H
S-(CH2)3CO2H
S-CH2CONHCH2CO2H
S-CH2SCH2CO2H
S-CH2OCH2CO2H
Me 7900
Me 18000
Me 22000
Me 270
Me 1100
Me 190
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Me 200
aValues represent the average of at least two experiments. bHighest concentration tested.
Stability of 23 in human, rat and dog liver microsomes was determined after incubation for 3h
at 3000 nM. High metabolic stability was observed in all three species. (Table 3). Compounds 22
and 23 were simultaneously administered orally to rats (compound dosed at 2 mg/kg) and
plasma samples from the portal and jugular veins were analyzed for 22 and 23 (Table 3).
Although relatively low plasma levels were observed after oral dosing of 22 and 23, both
compounds were orally absorbed.22

Table 3. Stability of 23 in liver microsomes and plasma concentrations of 22 and 23, after oral
dosing to rats
Time
% Remaininga
Human
> 90
Rat
Dog
> 90
1 h
> 90
Cmpd
Plasma Concentration (M)
Systemic
Portal
3 h
1 h
3 h
1 h
22
23
0.27
0.20
0.41
0.38
0.12
0.10
0.34
0.34
aPercent of 23 remaining after 3h incubation with liver microsomes at 3000 nM concentration.
A hit to lead process for the HTS hit 1 resulted in lead compounds 22 and 23. Compound 23 is a
potent, competitive antagonist with a KB = 94 nM for inhibition of ADP-induced platelet
aggregation. It exhibits high metabolic stability in human, rat and dog liver microsomes and is
orally absorbed, although plasma levels after oral dosing to rats is low. The half-life (t1/2), Cmax
and Caco-2 permeability for analog 23 was found to be 1.2 h, 0.12 M, and 1.66 x10-7 cm/sec
24
respectively
. These data demonstrate that the structural class presented here, which
contains compounds 22 and 23, is a promising starting point for extensive lead optimization.
The optimization of 23 to lead compounds BX 667 and BX 048 will be reported in Part II of this
series.
Acknowledgement. We thank the Berlex Compound Logisitc and Parallel Synthesis Groups for
providing compound samples for testing, and the DMPK group for metabolism and
pharmacokinetic studies.
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22. Oral bioavailability can be limited by several factors including low solubility,
presystemic lability, low permeability, and first-pass metabolism. Established in vitro
and in vivo model systems are useful to assess whether a compound has properties
favorable for absorption/bioavailability in humans. Fasted male Sprague-Dawley rats
were used in these studies. Compounds 22 and 23 (2 mg/kg) was administered in a PEG
based vehicle (PEG 300/EtOH/Water: 94/4/2) by oral gavage (po). Following dosing,
blood samples were collected through the sampling cannula (0-24 hours post -dose).
Following collection, the blood samples were centrifuged and plasma was harvested.
The plasma samples were kept frozen until analysis.

23. Arunlakshana, O.; Schild, H. O. Br. J. Pharmacol. Chemother. 1959;14:48
24. Bioavailability (F) was not determined

O
N
O
O
H
H
N
N
N
N
O
O
N
O
O
N
O
O
O
OH
1
23
IC50 = 860 nM
F(rat) =45%
t1/2 =1.8h
IC50 = 86 nM
t1/2 =1.2h

Highlights:

A hit to lead process to discover reversible, orally available ADP receptor (P2Y12) antagonists has
been described



Parallel synthesis, methyl scan of the hit enhances the discovery of new analogs
Exploratory SAR provided orally available competitive reversible antagonist of P2Y12 receptor
Two analogs show high metabolic stability in liver microsomes and found to be orally absorbed