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. 2018 Feb 15;26(4):798-814.
doi: 10.1016/j.bmc.2017.12.015. Epub 2017 Dec 9.

Design and Synthesis of a Potent, Highly Selective, Orally Bioavailable, Retinoic Acid Receptor Alpha Agonist

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Free PMC article

Design and Synthesis of a Potent, Highly Selective, Orally Bioavailable, Retinoic Acid Receptor Alpha Agonist

Earl Clarke et al. Bioorg Med Chem. .
Free PMC article

Abstract

A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARβ, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARβ (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.

Figures

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Fig. 1
Fig. 1
RARα agonists and antagonist.
Scheme 1
Scheme 1
4-(3,5-Dichloro-4-alkoxy-benzamido)benzoic acids. (Reagents and conditions: (i) K2CO3, R1Br, DMF, 80 °C, 3 h; (ii) LiOH, THF, H2O, room temp, 12 h; (iii) (COCl)2,CH2Cl2, DMF, 0 °C, 1 h then methyl 4-amino-2-R2-benzoate, NEt3, room temp, 12 h or HATU, DMF, DIPEA, 5 min, then methyl 4-amino-2-R2-benzoate, DMF, room temp, 18 h; (iv) R1 = Bn, R2 = Me; BCl3, CH2Cl2, 0 °C then room temp, 12 h; (v) 1,1-di-tert-butoxy-N,N-dimethylmethanamine, toluene, 80 °C, 3 h, then room temp, 12 h; (vi) 1,1-di-tert-butoxy-N,N-dimethylmethanamine, toluene, 80 °C, 3 h, then further 1,1-di-tert-butoxy-N,N-dimethylmethanamine, 2 mol, added, 80 °C, 16 h. (vii) H2, Pd/C, MeOH, room temp; (viii) R1 = Et, R2 = MeO, R = tBu; BCl3, CH2Cl2, 0 °C then room temp 2 h).
Scheme 2
Scheme 2
4-(3,5-Dichloro-4-ethoxyphenylcarbamoyl)benzoic acid. (Reagents and conditions: (i) (COCl)2,CH2Cl2, DMF, 0 °C, then room temp 2 h; (ii) DIPEA, CH2Cl2, room temp, 16 h, then LiOH, THF, H2O, room temp, 16 h; (iii) K2CO3, EtI, DMF, 65 °C, 18 h, then further EtI, 70 °C, 3 h; (iv) LiOH, THF, H2O, room temp, 5 h).
Scheme 3
Scheme 3
4-(3,4,5-Trialkoxybenzamido)benzoic acids. (Reagents and conditions: (i) NaHCO3, R1I, DMF, 30 °C, 72 h; (ii) K2CO3, R2Br, DMF, 50 °C, 48 h; (iii) LiOH, THF, H2O, room temp, 16 h; (iv) (COCl)2, CH2Cl2, DMF, 0 °C, 1 h then methyl 4-amino-benzoate, NEt3, room temp, 12 h).
Scheme 4
Scheme 4
4-(3-Chloro-4,5-dialkoxybenzamido)benzoic acids with identical alkoxy groups. (Reagents and conditions: (i) BBr3, CH2Cl2, 0 °C, 2 h; (ii) TMSCl, MeOH, 50 °C, 16 h; (iii) K2CO3, RI, DMF, 70 °C, 46 h; (iv) LiOH, THF, H2O, room temp, 18 h; (v) (COCl)2, CH2Cl2, DMF, 0 °C, 1 h then methyl 4-amino-2-R1-benzoate, NEt3, room temp, 12 h).
Scheme 5
Scheme 5
4-(3-Chloro-4,5-dialkoxybenzamido)benzoic acids with non-identical alkoxy groups. (Reagents and conditions: (i) BBr3, CH2Cl2, 0 °C, 2 h; (ii) TMSCl, MeOH, 50 °C, 16 h; (iii) K2CO3, BnBr, DMF, 60 °C, 0.75 h; (iv) K2CO3, R2Br, DMF, 60 °C, 2 h; (v) H2, 10% Pd/C, MeOH; (vi) K2CO3, DMF, 60 °C, 10 min, then R3I, 40 °C, 3 h; (vii) LiOH, THF, H2O, 40 °C, 1 h, then room temp, 16 h; (viii) T3P, methyl 4-amino-2-R1-benzoate, NEt3, EtOAc, 60 °C, 4 h, then room temp, 16 h. (ix) LiOH, THF, H2O, 40 °C, 16 h).
Fig. 2
Fig. 2
Cresset FieldScreen representation of bioactive conformation of AM580. (Blue field points (spheres) highlight energy minima for a positively charged probe, red for a negative probe. Yellow spheres represent an attractive van der Waals minima for a neutral probe and orange spheres represent hydrophobic centroids. Oxygen atoms are shown in red, nitrogen in blue. The size of the points is related to the strength of the interaction).
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