Retinoidal pyrimidinecarboxylic acids. Unexpected diaza-substituent effects in retinobenzoic acids

Several pyridine- and pyrimidine-carboxylic acids were synthesized as ligand candidates fur retinoid nuclear receptors, retinoic acid receptors (RARs) and retinoic X receptors (RXRs), Although the pyridine derivatives, 6-[(5,6,7.8-tetrahyro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]pyridine-3-carboxylic acid (2b) and 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carboxamido]pyridine-3-carboxylic acid (5b) are more potent than the corresponding benzoic acid-type retinoids, Am80 (2a) and Am580 (5a), the replacement of the benzene ring of Am580 (5a), Am555 (6a), or Am55 (7a) with a pyrimidine ring caused loss of the retinoidal activity both in HL-60 cell differentiation assay and in RAR transactivation assay using COS-1 tells. On the other hand, pyrimidine analogs (PA series, 10 and 11) of potent RXR agonists (retinoid synergists) with a diphenylamine skeleton (DA series. 8 and 9) exhibited potent retinoid synergistic activity in HL-60 cell differentiation assay and activated RXRs, Among the synthesized compounds, 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)amino]pyrimidine-5-carboxylic acid (PA013, 10c) is most active retinoid synergist in HL-60 assay.