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. 2012 Jun 1;22(11):3739-42.
doi: 10.1016/j.bmcl.2012.04.023. Epub 2012 Apr 13.

Synthesis and SAR of tetrahydroisoquinolines as Rev-erbα agonists

Romain Noel  1 , Xinyi Song, Youseung Shin, Subhashis Banerjee, Douglas Kojetin, Li Lin, Claudia H Ruiz, Michael D Cameron, Thomas P Burris, Theodore M Kamenecka
Affiliations

Synthesis and SAR of tetrahydroisoquinolines as Rev-erbα agonists

Romain Noel et al. Bioorg Med Chem Lett. .

Abstract

The design and synthesis of a novel series of Rev-erbα agonists is described. The development and optimization of the tetrahydroisoquinoline series was carried out from an earlier acyclic series of Rev-erbα agonists. Through the optimization of the scaffold 1, several potent compounds with good in vivo profiles were discovered.

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Figures

Figure 1
Figure 1
Rev-erbα lead identified in FRET assay.
Figure 2
Figure 2
Cyclization Approach to Tetrahydroisoquinoline Analogues.
Scheme 1
Scheme 1
Synthesis of Tetrahydroisoquinoline Analogs Reagents and Conditions: (a) RCOCl, TEA, CH2Cl2; (b) RSO2Cl, pyr, CH2Cl2; (c) RNCO, toluene; (d) ClCO2R, DIEA, CH2Cl2; (e) RCHO, NaBH(OAc)3, ClCH2CH2Cl.
Scheme 2
Scheme 2
Modifications to C-3 Ester Reagents and Conditions: (a) LiBH4, MeOH; (b) R1Br, NaH or R1OH, PPh3, DIAD or AcCl, pyr; (c) LiOH, THF; (d) R4NH2, HATU, DIEA; (e) 1. (PhO)2P(O)(N3), PPh3, THF; 2 Pd/C, H2; (f) R2OCOCl or R3SO2Cl, Et3N or R2CHO, NaBH(OAc)3.
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