Syntheses of isotopically labeled 4‐[1‐(3,5,5,8,8‐pentamethyl‐5,6,7,8‐tetrahydro‐2‐naphthyl)ethenyl]benzoic acid (LGD1069), a potent retinoid x receptor‐selective ligand

Abstract

LGD1069,4-[ 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyi] benzoic acid, is the first retinoid X receptor (RXR) selective retinoid to enter clinical trials for treatment of dermatological diseases and cancer. In order to examine biological properties such as receptor binding, metabolism and bioavailability, [ I 'C]-. I14C]-, and [3H]-labeled LGD1069 is required. Herein, we describe synthetic methods for preparing isotopically labeled homologs of LGD1069 as well as comparative competition binding data for [6,7-3H]-LGD1069 and [3H]-9-cis retinoic acid with RXR active retinoids. The final radiolabeled products, [6,7-3H]-LGD 1069 and 3-[14C]-LGD1069 have specific activities of 56 Ci/mmol and 49 mCi/mmol, respectively. Radiochemical purities are 99.5% for [6,7-3H]-LGDlO69 and 99.0% for 3-[14C]-LGD1069. The chemical purity is 99.0% for 3-['3CD3]-LGD1069. Competition binding studies with known retinoids show similar Q values when either [6,7-3H]-LGD1069 or [3H]-9-cis retinoic acid is used as the radioligand.

A novel gene expression analytics-based approach to structure aided design of rexinoids for development as next-generation cancer therapeutics

“…However, in the studies presented here, cells were treated only with bexarotene analogs which indicates that the analogs are regulating receptor dynamics independent of vitamin D binding. These findings are consistent with previous reports that indicate that the RXRα/VDR heterodimer may act as a permissive receptor, at least in some cases [67,68]. Conformational changes of the RXRα/VDR dimer induced solely by 9-cis-retinoic acid (9-cis-RA) binding are thought to enhance VDR-DBD stability and may facilitate interactions with co-regulatory proteins such as SRC1-RID [67].…”

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR) Selective Agonists: Novel Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic Acid (CD3254)

“…To synthesize a sample of compound 10 , a modified literature procedure 37 was used. Toluene was reacted with dihydro-2,2,5,5-tetramethylfuran-3(2 H )-one ( 32 ) with aluminum chloride as a catalyst to provide 3,4-dihydro-1,1,4,4,7-pentamethylnaphthalen-2(1 H )-one ( 33 ) 37 in 44% yield.…”

“…37 To a 100 mL round bottom flask charged with dihydro-2,2,5,5-tetramethylfuran-3(2 H )-one ( 32 ) (2.4 g, 17 mmol) and toluene (10.0 mL, 94 mmol) at 0 °C was added aluminum chloride (4.55 g, 34 mmol) in one portion with stirring. The reaction was stirred at 0 °C for 30 min, then warmed to room temperature and stirred for 2h, and then heated to 50-55 °C with stirring for 15 min.…”

“…Incorporating a pyridine ring, compound 8 36 has been reported to be equally potent as 1 , and substituting the alkene bridging group in 8 for a cyclopropyl bridging group yields LGD100268 ( 9 ) 36 , with a reported potency one order of magnitude greater than 1 in a CV-1 cell line. 36 An unsaturated analog of 1 , compound 10 37 , has a reported synthetic route that can provide preclinical trial quantities 38 , though to our knowledge, the ability of 10 to bind and activate RXR has not been reported. Finally, acrylic acid 11 39 demonstrates potent, selective RXR agonism, and acrylic acid CD2915 ( 12 ) 40 is also a known RXR agonist.…”

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB)

“…The acrylic acids 10 (CD3254) [61] and 11 (CD2915) [62] possess similar potency for RXR agonism as 1. Compound 12 [63,64] possesses a single unsaturation in the aliphatic ring system as its only structural difference from 1. We used compounds 8-12 as starting points to prepare analogous rexinoids 13-19 [21] with unique gene expression and side-effect profiles in vivo [65].…”