Nonsteroidal progesterone receptor ligands (II); synthesis and SAR of new tetrahydrobenzindolone derivatives

The human progesterone receptor (PR) binding affinity and the PR agonistic or antagonistic potency of tetrahydronaphthofuranone derivatives were shown previously to be markedly influenced by substituents at the 6- and 7-positions. Here, we synthesized tetrahydrobenzindolones possessing a lactam ring, which enabled us to modify the 6- and 7-positions more freely, since tetrahydrobenzindolones are chemically more stable than tetrahydronaphthofuranones. The tetrahydrobenzindolone derivatives generally showed higher PR binding affinity than the corresponding tetrahydronaphthofuranones. We also succeeded in separating the agonistic and antagonistic activities by choosing suitable substituent groups at the 6- and/or 7-position(s) of the tetrahydrobenzindolone. The effects of representative agonists, 12c (CP8668), and 14a (CP8816), and a representative antagonist, 15f (CP8661), were confirmed in in vivo tests. In this report, we mainly describe the synthesis and structure–activity relationships (SAR) of tetrahydrobenzindolone derivatives, as new nonsteroidal PR ligands.

We have developed a new lead compound, tetrahydrobenzindolone, possessing a lactam ring, which shows sufficient stability for easy modification at the 6- and/or 7-positions. We succeeded in separating the agonistic and antagonistic activities by choosing suitable substituent groups at the 6- and/or 7-position(s) of the tetrahydrobenzindolone.Figure optionsDownload as PowerPoint slide