Indomethacin morpholinyl amide (343) was found as a weak but CB2 selective agonist through a topological similarity search using WIN 55,212-2 (254a) as the template . The binding affinity (K) of (343) was 435 and >20,000 nM for hCB2 and hCB1, respectively. A subsequent SAR study revealed that N-(2,3-dichlorobenzoyl) and N-naphthoyl indole derivatives showed improved activity. Further optimisation of the substituents on the indole C3-position was also performed, and the more selective and potent CB2 agonists, L-768,242 (344) and L-759,787 (345) were discovered. These compounds showed >100-fold CB2 selectivity with significant potency (K of 12 and 8.5 nM, respectively).
(344) L-768,242 X = -(CH2)2-, R1 = OMe, R2 = 2,3-diCl-phenyl K^hCB,) = 1917nM, Ki(hCB2) = 12nM
(345) L-759,787 X = -CH2-, R1 = H, R2 = 1-naphthyl Ki(hCB1) = 877nM, ^(hCB2) = 8.5nM
During the study of N-alkylindole derivatives as cannabinoid ligands, JWH-015 (346) was found as a potent CB2 selective agonist, Ki (CB2) 13.8 nM with modest selectivity, (CBi): (CB2) = 28 . For the optimisation study of (346), more than 40 indoles were prepared and their CB1 and CB2 receptor affinities were determined . In most cases, N-pentyl indoles showed significant activity but low receptor subtype selectivity, whereas N-propyl derivatives had better selectivity for CB2. The SAR of the substituents on the naphthyl ring was also studied, and it is noteworthy that introduction of a methoxy group in the 2-position of the naphthyl ring reduced the binding affinity only for the CB1 receptor, even though the compound bears a pentyl group on the indole ring. As a result, three CB2 selective compounds, JWH-120 (347), JWH-151 (348) and JWH-267 (349) were found; JWH-151 was a full agonist whereas JWH-120 and JWH-267 exhibited partial activity in GTPgS binding assay.
(346) JWH-015 R1 = n-Pr, R2 = R3 = R4 = H Ki(CB1) = 383nM, Ki(CB2) = 13.8nM
(347) JWH-120 R1 = n-Pr, R2 = R4 = H, R3 = Me Ki(CB1) = 1054nM, K|(CB2) = 6.1nM
(348) JWH-151 R1 = n-Pr, R2 = R3 = H, R4 = OMe Ki(CB1) >10,000nM, K|(CB2) = 30nM
(349) JWH-267 R1 = n-C5H11, R2 = OMe, R3 = R4 = H R' Ki(CB1) = 381nM, K|(CB2) = 7.2nM
The group of Bristol-Myers Squibb found a C3 amido-indole (350) as a lead compound for their CB2 agonist program . Compound (350) demonstrated moderate binding affinity for CB2 (K 250 nM), which was improved dramatically to a Ki of 8 nM by the introduction of methoxy group on the C7 of the indole core. The 7-methoxy indole (351) showed good receptor subtype selectivity, CB1 : CB2 = 500, however, the methyl ester on the phenylalanine moiety was susceptible to microsomal hydrolysis. In an effort to discover non-ester CB2 agonists, compound (352), having a (1S)-fenchyl group instead of the phenylalanine methyl ester, was prepared. The introduction of a larger alkyl group onto the C2 position of the indole ring decreased the CB2 binding affinity (H>Me>Et> n-Pr; Table 6.33). The non-substituted compound (353) showed dose-dependent inhibitory activity in an in vivo anti-inflammatory model [lipopolysaccharide (LPS)-induced TNF-a production in mice] after i.v. administration with an ED50 of 5mg/kg. Unfortunately, (353) was inactive after oral administration, and
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