- HETEROCYCLIC CARBOXYLIC ACID DERIVATIVES
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Compounds or salts thereof represented by the formula (I) wherein R1 represents hydrogen atom, a C1-6 alkyl group, a C1-6 alkenyl group, or an acyl group, R2 and R3 represent hydrogen atom or a C1-6 alkyl group, or adjacent R2 and R3 may combine to form 5- to 7-membered ring, R4 represents hydrogen atom, hydroxyl group, a C1-6 alkoxyl group, a C1-6 alkyl group, HAr represents a heteroaryl-diyl group consisting of a 5-membered or 6-membered ring containing 1 to 3 hetero atoms, R5 represents hydrogen atom or a C1-6 alkyl group. The compounds or the salts thereof have retinoid-like physiological activities or controlling activity on physiological activities of retinoid.
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- Retinoidal pyrimidinecarboxylic acids. Unexpected diaza-substituent effects in retinobenzoic acids
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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]pyridine- 3-carboxylic acid (2b) and 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]pyridin e-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)amino] pyrimidine-5-carboxylic acid (PA013, 10e) is most active retinoid synergist in HL-60 assay.
- Ohta, Kiminori,Kawachi, Emiko,Inoue, Noriko,Fukasawa, Hiroshi,Hashimoto, Yuichi,Itai, Akiko,Kagechika, Hiroyuki
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p. 1504 - 1513
(2007/10/03)
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