Expansion of SAR studies on triaryl bis sulfone cannabinoid CB2 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2010.08.126

We report further expansion of the structure activity relationship (SAR) on the triaryl bis sulfone class of compounds (I), which are potent CB₂ receptor ligands with excellent selectivity over the CB₁ receptor. This study was extended to B ring changes, followed by simultaneous optimization of the A-, B-, and C-rings. Compound 42 has excellent CB₂ potency, selectivity and rat exposure.

Full text of DOI:10.1016/j.bmcl.2010.08.126

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6785–6789
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Expansion of SAR studies on triaryl bis sulfone cannabinoid CB2 receptor ligands
Ling Tong a, , B. B. Shankar a, , Lei Chen a, Razia Rizvi a, Joseph Kelly a, Eric Gilbert a, Chunli Huang a,
De-Yi Yang a, Joseph A. Kozlowski a, N.-Y. Shih a, W. Gonsiorek b, R. William Hipkin b, Asra Malikzay c,
Charles A. Lunn c, Daniel J. Lundell b
⇑
⇑
a Department of Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
b Department of Immunology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
c New Lead Discovery, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2010
Revised 23 August 2010
Accepted 25 August 2010
Available online 31 August 2010
We report further expansion of the structure activity relationship (SAR) on the triaryl bis sulfone class of
compounds (I), which are potent CB2 receptor ligands with excellent selectivity over the CB1 receptor.
This study was extended to B ring changes, followed by simultaneous optimization of the A-, B-, and
C-rings. Compound 42 has excellent CB2 potency, selectivity and rat exposure.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Inverse agonists
Cannabinoid receptor
CB2
SAR
There is an increasing appreciation of the therapeutic value of
inverse agonists as drugs. b-Adrenoceptor inverse agonists may
be useful in the chronic treatment of asthma, lacking the detrimen-
tal effects of chronic use of b2-adrenoceptor agonists.1 GABAA
compounds.6a,b In these studies we optimized the benzylic methyl
group and its stereochemistry (R preferred), nature of linkers (SO2
was optimal), and variations to the C ring, (Fig. 1). These efforts led
to 1, a potent and selective compound with acceptable PK param-
eters.6c We recently reported SAR studies on A ring modifications.9
In this communication, we report extension of the SAR studies to
heterocyclic replacements of the B ring and analogs with simulta-
neous optimization of the A-, B-, C-rings, generic structure I. These
efforts culminated in structurally novel ligands with very good po-
tency, selectivity, and rat PK.
receptor
a5 subtype-selective inverse agonists may be valuable
in the treatment of cognitive performance in disorders in Alzhei-
mer’s disease and schizophrenia.2 Evidence for in vivo constitutive
activity of the serotonin2A and 2C receptors suggest that inverse
agonists will be valuable in the treatment of schizophrenia, anxi-
ety, weight control and Parkinsonism.3 Studies with cannabinoid
CB1 receptor-specific inverse agonists have shown clinical efficacy,
though side effects proved unacceptable.4
The two generic routes employed to access these compounds
are shown in Schemes 1 and 2.
Several class of compounds including pyrazoles, oxoquinolines
and more recently imidazoles have been reported as highly recep-
tor-specific ligands to cannabinoid CB2 receptor.5 We are develop-
ing chemistry around a class of triaryl bis sulfone ligands that
behave as inverse agonists to the CB2 receptor.6 These ligands were
shown to modulate antigen-induced lung eosinophilia,7 antigen-
induced bone loss and peptide-induced experimental autoimmune
encephalomyelitis8, and thus may be useful in several therapeutic
indications.
The first route required treating the lithiated heterocycle II (ob-
tained by either extracting the most acidic proton or by halogen-
metal exchange of brominated heterocycle) with sulfonyl fluoride
2.6c The sulfone group in III then directed the next lithiation (with
2 equiv of nBuLi) to the ortho position of the B ring and the
resulting lithio species was quenched with a disulfide or sulfonyl
Previously we described discovery of a novel triaryl bisulfone
CB2 selective inhibitor, and SAR studies optimizing this class of
⇑
Corresponding authors. Tel.: +1 908 740 4185 (L.T.); tel.: +1 908 740 3460;
fax: +1 908 740 7305 (B.B.S.).
E-mail addresses: ling.tong@spcorp.com (L. Tong), bandarpalle.shankar@spcorp.-
com (B.B. Shankar).
Figure 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.126

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L. Tong et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6785–6789
Scheme 1.
Scheme 3. Reagents and conditions: (a) (i) nBuLi, THF, À78 °C, SO2; (ii) NCS, CH2Cl2,
rt; (iii) KF, acetone/H2O, rt; (b) nBuLi, THF, À78 °C, 2 (55%); (c) (i) LiOH, dioxane; (ii)
(C2H5)3N, (CF3SO2)2O, À78 °C; (d) NaOH (aq 1 N), CH2Cl2, tetrabutylammonium
hydrogensulfate (cat.), rt (35%).
Scheme 2.
fluoride to provide IV. With the disulfide quench, an additional
oxidation step to sulfone was required. Base hydrolysis followed
by derivatization with trifluoromethanesulfonic anyhdride
provided V.
Scheme 4. Reagents and conditions: (a) NaOH (aq 1 N), toluene, tetrabutylammo-
nium hydrogensulfate (cat.), rt; (b) (i) nBuLi, THF, À78 °C, SO2; (ii) NCS, CH2Cl2, rt;
(45%); (c) (C2H5)3N, CH2Cl2, rt.
Alternatively, B and C rings were assembled first, employing
lithiation followed by sulfonylhalide quench as described above.
The biaryl sulfone VI was lithiated directly with n-BuLi and the
resulting lithio species reacted with sulfonyl fluoride VII, providing
VIII which can then be processed as described above (III to IV) to
provide IX.
Specific chemistry to access indole derivative 6, is described in
Scheme 3. N-Boc indole was selectively lithiated at 2-position and
treated with sulfonyl fluoride 2 to provide compound 4. Base pro-
moted hydrolysis of the trifluormethyl acetamide group followed
by sulfonylation with trifluoromethylsulfonic anhydride in the
presence of a base at À78 °C provided selectively derivatized 5.
The C ring was installed by treating 5 with 2-fluorophenylsulfonyl
chloride under phase transfer conditions, providing 6.
Chemistry to access analogs such as 12 where the A ring is
piperidine and B ring is indole, is shown in Scheme 4. The indole
NH was sulfonylated with aryl sulfonyl chloride 8, under phase
transfer conditions using aqueous base, to provide 9. Regioselec-
tive lithiation at the 2-position of indole 9 followed by SO2 quench
and chlorination with N-chlorosuccinimde of the resulting sulfonic
acid resulted in the sulfonyl chloride 10. This reagent reacted with
piperidine derivative 11,9 in the presence of a base to provide the
target 12.11
alternates to the p-chloro-phenyl of 1 (entries: 6, 13, and 14). All of
them showed diminished activity compared to 1. Keeping the ease
of synthesis in mind, and the desire to change the B-ring, the indole
ring was selected for further investigation.
With the B ring fixed as an indole and C ring as 2-fluorophenyl,
we explored the SAR around the A ring to restore potency for CB2. A
variety of cyclic amines were examined (12, 15, 16, 17, and 18). A
4-substituted piperidine ring was well tolerated, that is, 12. Next, a
variety of piperidine analogs which maintained a substituent in the
4-position of the piperidine were investigated (entries 19–31).
Additional substitutions at 3- and 4-positions were often tolerated,
with marginal decrease in selectivity (entries 21–26). Other substi-
tution patterns led to diminished potency and selectivity (entries
27–31). Now, selecting the A ring as unsubstituted 4-piperidinyl
methyl while keeping the C ring as 2 F-phenyl, we revisited the B
ring SAR. Substituted indole, aza indole, reverse indole, furan and
pyridyl ring were synthesized and evaluated (entries 32–36). Be-
sides the substituted indole, aza indole and furan ring were toler-
ated. However, none of them were superior to the simple indole
ring (compound 12). Based on our earlier work in the triphenyl sul-
fone series,6b we found 2-pyridyl to be well tolerated. Several pyr-
idyl isomers were explored here (entries 37–39) with the 2-pyridyl
preferred. Finally, three point changes by incorporating optimized
A, B, and C rings provided us with very potent and selective com-
pounds (entries 40–43).
All the compounds shown in Table 1 were accessed by the
chemistry exemplified above. SAR was developed to identify B ring

L. Tong et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6785–6789
6787
Table 1
Compound
Synthesis scheme
1
B ring
C ring
A ring
Kia,15 CB2 (nM)
Selectivity KiCB1/KiCB2
1
6
0.7
2273
1338
962
3
1
1
7.5
8.4
4.4
13
14
2686
15
4
258
3
16
17
18
12
4
4
4
4
452
117
12
8430
249
11
0.38
9250
19
20
21
22
4
4
4
4
0.4
2077
64
171
0.2
4375
6720
0.35
23
4
1.8
2525
(continued on next page)

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L. Tong et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6785–6789
Table 1 (continued)
Compound
Synthesis scheme
4
B ring
C ring
A ring
Kia,15 CB2 (nM)
Selectivity KiCB1/KiCB2
24
78
24
25
26
27
28
29
30
4
4
4
4
4
4
0.5
1.5
16
4.2
3.1
1
2256
6666
334
245
630
413
31
4
9
279
32
34
4
4
0.8
70
5161
364
35
36
37
1
1
4
1.4
790
0.9
4524
126
9177
38
39
40
4
4
4
41
23
0.4
139
126
3500

L. Tong et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6785–6789
6789
Table 1 (continued)
Compound
Synthesis scheme
4
B ring
C ring
A ring
Kia,15 CB2 (nM)
Selectivity KiCB1/KiCB2
4112
0.4
2797
26,378
3199
4213
4
4
1.6
2.5
4314
a
Individual data points for determinations of Ki for CB1 and CB2 were carried out in triplicate, in two separate assays.
6. (a) Lavey, B. J.; Kozlowski, J.; Hipkin, R. W.; Gonsiorek, W.; Lundell, D. J.;
Piwinski, J.; Narula, S.; Lunn, C. A. Bioorg. Med. Chem. Lett. 2005, 15, 783; (b)
Shankar, B. B.; Lavey, B. J.; Zhou, G.; Spitler, J. A.; Tong, L.; Rizvi, R.; Yang, D.-Y.;
Wolin, R.; Kozlowski, J. A.; Shih, N.-Y.; Wu, J.; Hipkin, R. W.; Gonsiorek, W.;
Lunn, C. A. Bioorg. Med. Chem. Lett. 2005, 15, 4417; (c) Lavey, B. J.; Kozlowski, J.
A.; Shankar, B. B.; Spitler, J. M.; Zhou, G.; Yang, D.-Y.; Shu, Y.; Wong, M. K.;
Wong, S. C.; Shih, N. Y.; Wu, J.; McCombie, S. W.; Rizvi, R.; Wolin, R. L.; Lunn, C.
A. Bioorg. Med. Chem. Lett. 2007, 17, 3760.
7. Lunn, C. A.; Fine, J. S.; Rojas-Triana, A.; Jackson, J. V.; Fan, X.; Kung, T. T.;
Gonsiorek, W.; Schwarz, M. A.; Lavey, B. J.; Kozlowski, J. A.; Narula, S. K.;
Lundell, D. J.; Hipkin, R. W.; Bober, L. A. J. Pharmacol. Exp. Ther. 2006, 316, 780.
8. Lunn, C. A.; Reich, E. P.; Fine, J. S.; Lavey, B.; Kozlowski, J. A.; Hipkin, R. W.;
Lundell, D. J.; Bober, L. Br. J. Pharmacol. 2008, 153, 226.
Table 2
Compound
Rat AUC nM h (10 mpk)
12
40
41
42
43
3900
4559
3767
17,555
3191
9. Gilbert, E. J.; Zhou, G.; Wong, M. K. C.; Tong, L.; Shankar, B. B.; Huang, C.; Kelly,
J.; Lavey, B. J.; McCombie, S. W.; Chen, L.; Rizvi, R.; Dong, Y.; Shu, Y.; Kozlowski,
J. A.; Shih, N.-Y.; Hipkin, W.; Gonsiorek, W.; Lunn, C. A.; Lundell, D. J. Bioorg.
Med. Chem. Lett. 2010, 20, 608.
Selected compounds were dosed in rats for pharmacokinetic
evaluations.16 The exposure levels attained for compounds 12,
40–43 at 10 mg/kg dose in 20% (w/v) hydroxypropyl b cyclodex-
trin, are shown in Table 2.
In conclusion, we expanded the SAR of compound 1 by selecting
the indole ring as a B-ring surrogate, and second by optimizing the
SAR in an iterative fashion through A- and C-ring changes. These
efforts culminated in identification of compounds (Table 2) which
are structurally very different than 1, which have comparable po-
tency and selectivity for CB2, and are currently under going further
evaluation.
10. McGuinness, D.; Malikzay, A.; Visconti, R.; Lin, K.; Bayne, M.; Monsma, F.; Lunn,
C. A. J. Biomol. Screening 2009, 14, 49.
11. Compound 12: 1H NMR (CDCl3) d 8.25 (d, J = 9.3 Hz, 1H), 8.03 (dt, J = 1.6 Hz,
7.0 Hz, 1H), 7.64 (d, J = 8 Hz, 1H), 7.51–7.60 (m, 2H), 7.47 (b, 1H), 7.37 (t,
J = 7.7 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 7.05 (t, J = 9.6 Hz, 1H), 5.6 (b, 1H), 3.95 (d,
J = 13 Hz, 2H), 3.19 (d, J = 6.6 Hz, 2H), 2.84 (t, J = 11.5 Hz, 2H), 1.81 (d,
J = 13.3 Hz, 2H), 1.70 (m, 1H), 1.35 (dt, J = 4.0 Hz, 11.6 Hz, 2H).
12. Compound 41: 1H NMR (CDCl3) d 8.23 (m, 1H), 8.02 (m, 1H), 7.58 (m, 1H), 7.42
(s, 1H), 7.25 (m, 3H), 7.04 (m, 1H), 5.17 (t, J = 6.6 Hz, 1H), 3.42 (m, 2H), 3.33 (m,
2H), 3.19 (d, J = 6.6 Hz, 2H), 1.54 (m, 4H), 1.42 (q, J = 7.0 Hz, 2H), 0.83 (t,
J = 7.0 Hz, 3H).
13. Compound 42: 1H NMR (CDCl3) d 8.5 (d, J = 4 Hz, 1H), 8.4 (d, J = 6 Hz, 1H), 8.2 (d,
J = 6 Hz, 1H), 7.9 (m, 1H), 7.62 (d, 1H), 7.4–7.6 (m, 3H), 7.36 (m, 1H), 3.5 (m,
2H), 3.38 (m, 2H), 3.19 (d, J = 6.6 Hz, 2H), 1.58 (m, 4H), 1.38 (m, 2H), 1.2 (m,
4H).
Acknowledgement
14. Compound 43: 1H NMR (CDCl3) d 8.40 (d, J = 7.0 Hz, 1H), 8.23 (m, 1H), 7.97 (d,
J = 10 Hz, 1H), 7.58 (m, 1H), 7.30 (m, 1H), 7.22 (m, 1H), 7.02 (m, 1H), 5.40 (b,
1H), 3.70 (d, J = 15 Hz, 2H), 3.25 (m, 4H), 3.20 (s, 3H), 1.96 (d, J = 15 Hz, 2H),
1.66 (m, 2H).
We thank Dr. J. Palamanda for pharmacokinetic evaluations.
References and notes
15. Compounds 1, 6, 12 and 42 were tested for the ability to modulate interaction
between a recombinant cannabinoid CB2 receptor and b-arrestin, using the
PathHunter™ protein complementation assay (DiscoveRx Corporation).
Previous studies showed that this system correctly predicts the
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2. Atack, J. R. Pharmacol. Ther. 2010, 125, 11.
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a number of cannabinoid CB2 agonists and inverse
3. Aloyo, V. J.; Berg, K. A.; Spampinato, U.; Clarke, W. P.; Harvey, J. A. Pharmacol.
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agonists.10 Test compounds behaved as inverse agonists in a manner similar
to compound 1, decreasing the constitutive ability of the cannabinoid CB2
receptor to interact with b-arrestin. As expected, the agonist WIN55212-2
increases this interaction.
16. Korfmacher, W. A.; Cox, K. A.; Ng, K. J.; Veals, J.; Hsieh, Y.; Wainhaus, S.; Broske,
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