Syntheses and evaluation of naphthalenyl- and chromenyl-pyrrolyl-benzoic acids as potent and selective retinoic acid receptor α agonists

https://doi.org/10.1016/S0960-894X(00)00067-6Get rights and content

Abstract

Synthesis and structure–activity relationships (SAR) of RARα-selective agonists are discussed. 4-[5-(5,8-Dimethyl-2H-3-chromenyl)-1H-2-pyrrolyl]benzoic acid (12a), which possesses a flat structural moiety and an oxygen atom at the hydrophobic part, showed highly selective transactivation activity at the RARα receptor.

Section snippets

Chemistry

Naphthalenyl and benzopyranyl-pyrrolyl derivatives (11 and 12) were synthesized by the method of Scheme 1. The carbaldehydes (4 and 5), which were prepared by the reported method,4b were treated with vinyl Grignard reagent and oxidized with manganese(IV) oxide (activated) to afford enone derivatives (6 and 7). The enone derivatives (6 and 7) were coupled with methyl 4-formylbenzoate (8) to give the diketones (9 and 10). These derivatives (9 and 10) were treated with ammonium acetate to afford

Results and Discussion

The subtype-selective competitive binding and transactivation data are summarized in Table 1. The 5,8-dimethylnaphthalene derivative 11a did not show affinity for RARβ or RARγ, whereas it has moderate binding affinity for RARα. This compound (11a) is 3-fold less potent at RARα than ATRA, but was 250 and 2000-fold less potent at RARβ and RARγ, respectively. The mono 8-methyl derivative (11b) is less potent than the 5,8-dimethylnaphthalene derivative (11a) in transactivation activity for RARα.

References (6)

  • M Leid et al.

    Trends Biochem. Sci.

    (1992)
  • Mangelsdorf, D. J.; Umesono, K.; Evans, R. M. In The Retinoids; Sporn, M. B.; Roberts, A. B.; Goodman, D. S., Eds;...
  • Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tai, K.; Hida, T.; Tokuhara, N.; Ishibashi, A.; Yamauchi, T.; Nagai, M. Bioorg....
There are more references available in the full text version of this article.

Cited by (0)

View full text