Potent and selective [2-imidazol-1-yl-2-(6-alkoxynaphthalen-2-yi)-1-methyl-ethyl]-dimethyl-am ines as retinoic acid metabolic blocking agents (RAMBAs)

OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735, USA.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.42). 04/2005; 15(6):1669-73. DOI: 10.1016/j.bmcl.2005.01.044
Source: PubMed


A series of [2-imidazol-1-yl-2-(6-alkoxy-naphthalen-2-yl)-1-methyl-ethyl]-dimethyl-amines were designed and synthesized as CYP26 inhibitors, serving as retinoic acid metabolic blocking agents (RAMBA's).

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    • "The first tested inhibitors of atRA metabolism included liarozole (5-[(3-chlorophenyl)-1H-imidazol-1-ylmethyl]- 1H-benzimidazole hydrochloride, R75251) and ketoconazole that inhibited metabolism of atRA in vivo in rats and in in vitro models (Van Wauwe et al., 1988, 1990; Wouters et al., 1992). Subsequently, more specific and potent inhibitors of atRA metabolism synthesized by several groups showed potential for treatment of cancers and skin diseases in both in vitro and in vivo models (Patel et al., 2004; Mulvihill et al., 2005; Yee et al., 2005; Njar et al., 2006). CYP26A1 appears to be a likely target for development of new inhibitors of atRA metabolism. "
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    ABSTRACT: All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. atRA is also used as a drug, and synthetic atRA analogs and inhibitors of retinoic acid (RA) metabolism have been developed. The hepatic clearance of atRA is mediated primarily by CYP26A1, but design of CYP26A1 inhibitors is hindered by lack of information on CYP26A1 structure and structure-activity relationships of its ligands. The aim of this study was to identify the primary metabolites of atRA formed by CYP26A1 and to characterize the ligand selectivity and ligand interactions of CYP26A1. On the basis of high-resolution tandem mass spectrometry data, four metabolites formed from atRA by CYP26A1 were identified as 4-OH-RA, 4-oxo-RA, 16-OH-RA and 18-OH-RA. 9-cis-RA and 13-cis-RA were also substrates of CYP26A1. Forty-two compounds with diverse structural properties were tested for CYP26A1 inhibition using 9-cis-RA as a probe, and IC(50) values for 10 inhibitors were determined. The imidazole- and triazole-containing inhibitors [S-(R*,R*)]-N-[4-[2-(dimethylamino)-1-(1H-imidazole-1-yl)propyl]-phenyl]2-benzothiazolamine (R116010) and (R)-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2-benzothiazolamine (R115866) were the most potent inhibitors of CYP26A1 with IC(50) values of 4.3 and 5.1 nM, respectively. Liarozole and ketoconazole were significantly less potent with IC(50) values of 2100 and 550 nM, respectively. The retinoic acid receptor (RAR) γ agonist CD1530 was as potent an inhibitor of CYP26A1 as ketoconazole with an IC(50) of 530 nM, whereas the RARα and RARβ agonists tested did not significantly inhibit CYP26A1. The pan-RAR agonist 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid and the peroxisome proliferator-activated receptor ligands rosiglitazone and pioglitazone inhibited CYP26A1 with IC(50) values of 3.7, 4.2, and 8.6 μM, respectively. These data demonstrate that CYP26A1 has high ligand selectivity but accepts structurally related nuclear receptor agonists as inhibitors.
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    ABSTRACT: 3-[6-(2-Dimethylamino-1-imidazol-1-yl-butyl)-naphthalen-2-yloxy]-2,2-dimethyl-propionic acid and analogs were designed and synthesized as highly potent and selective CYP26 inhibitors, serving as retinoic acid metabolic blocking agents (RAMBAs), with demonstrated in vivo efficacy to increase the half-life of exogenous atRA.
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