Retinoidal pyrimidinecarboxylic acids. Unexpected diaza-substituent effects in retinobenzoic acids.
Several pyridine- and pyrimidine-carboxylic acids were synthesized as ligand candidates for retinoid nuclear receptors, retinoic acid receptors (RARs) and retinoic X receptors (RXRs). Although the pyridine derivatives, 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]pyri dine-3-carboxylic acid (2b) and 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]py ridine-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 cells. 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)a mino]pyrimidine-5-carboxylic acid (PA013, 10e) is most active retinoid synergist in HL-60 assay.
Ohta
K
K
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan.
Kawachi
E
E
Inoue
N
N
Fukasawa
H
H
Hashimoto
Y
Y
Itai
A
A
Kagechika
H
H
D000818:Animals; D019556:COS Cells; D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011743:Pyrimidines / Q000737:chemistry*; D012176:Retinoids / Q000737:chemistry* / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
D002264:Carboxylic Acids; D011743:Pyrimidines; D012176:Retinoids