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

Overview

Journal Bioorg Med Chem

Specialties Biochemistry
Chemistry

Date 2017 Dec 31

PMID 29288071

Citations 6

Authors

Earl Clarke

Christopher I Jarvis

Maria B Goncalves

S Barret Kalindjian

David R Adams

Jane T Brown

Jason J Shiers

David M A Taddei

Elodie Ravier

Stephanie Barlow

Iain Miller

Vanessa Smith

Alan D Borthwick

Jonathan P T Corcoran

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Teng M, Duong T, Klein E, PINO M, Chandraratna R . Identification of a retinoic acid receptor alpha subtype specific agonist. J Med Chem. 1996; 39(16):3035-8. DOI: 10.1021/jm9603532. View

Lu Y, Bertran S, Samuels T, Mira-y-Lopez R, Farias E . Mechanism of inhibition of MMTV-neu and MMTV-wnt1 induced mammary oncogenesis by RARalpha agonist AM580. Oncogene. 2010; 29(25):3665-76. PMC: 2891995. DOI: 10.1038/onc.2010.119. View

Hopkins A, Groom C, Alex A . Ligand efficiency: a useful metric for lead selection. Drug Discov Today. 2004; 9(10):430-1. DOI: 10.1016/S1359-6446(04)03069-7. View

Yamauchi T, Ishibashi A, Shikata K, Tokuhara N, Seino K, Kobayashi S . Effect of E6060 [4-{5-[7-fluoro-4-(trifluoromethyl)benzo[b]furan-2-yl]-1H-2-pyrrolyl}benzoic acid], a novel subtype-selective retinoid, on lupus-like nephritis in female (NZBxNZW)F1 mice. J Pharmacol Exp Ther. 2004; 312(3):938-44. DOI: 10.1124/jpet.104.075598. View

Kagechika H, Kawachi E, Hashimoto Y, Himi T, Shudo K . Retinobenzoic acids. 1. Structure-activity relationships of aromatic amides with retinoidal activity. J Med Chem. 1988; 31(11):2182-92. DOI: 10.1021/jm00119a021. View

Leid M, Kastner P, Chambon P . Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci. 1992; 17(10):427-33. DOI: 10.1016/0968-0004(92)90014-z. View

Elmazar M, Reichert U, Shroot B, Nau H . Pattern of retinoid-induced teratogenic effects: possible relationship with relative selectivity for nuclear retinoid receptors RAR alpha, RAR beta, and RAR gamma. Teratology. 1996; 53(3):158-67. DOI: 10.1002/(SICI)1096-9926(199603)53:3<158::AID-TERA3>3.0.CO;2-0. View

Jarvis C, Goncalves M, Clarke E, Dogruel M, Kalindjian S, Thomas S . Retinoic acid receptor-α signalling antagonizes both intracellular and extracellular amyloid-β production and prevents neuronal cell death caused by amyloid-β. Eur J Neurosci. 2010; 32(8):1246-55. PMC: 3003897. DOI: 10.1111/j.1460-9568.2010.07426.x. View

Vinter J, Trollope K . Multiconformational composite molecular potential fields in the analysis of drug action. I. Methodology and first evaluation using 5-HT and histamine action as examples. J Comput Aided Mol Des. 1995; 9(4):297-307. DOI: 10.1007/BF00125171. View

10.

Yoshimura H, Kikuchi K, Hibi S, Tagami K, Satoh T, Yamauchi T . Discovery of novel and potent retinoic acid receptor alpha agonists: syntheses and evaluation of benzofuranyl-pyrrole and benzothiophenyl-pyrrole derivatives. J Med Chem. 2000; 43(15):2929-37. DOI: 10.1021/jm000098s. View

11.

Altucci L, Leibowitz M, Ogilvie K, de Lera A, Gronemeyer H . RAR and RXR modulation in cancer and metabolic disease. Nat Rev Drug Discov. 2007; 6(10):793-810. DOI: 10.1038/nrd2397. View

12.

Cheeseright T, Mackey M, Rose S, Vinter A . Molecular field extrema as descriptors of biological activity: definition and validation. J Chem Inf Model. 2006; 46(2):665-76. DOI: 10.1021/ci050357s. View

13.

Bourguet W, Vivat V, Wurtz J, Chambon P, Gronemeyer H, Moras D . Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains. Mol Cell. 2000; 5(2):289-98. DOI: 10.1016/s1097-2765(00)80424-4. View

14.

Seino K, Yamauchi T, Shikata K, Kobayashi S, Nagai M, Taniguchi M . Prevention of acute and chronic allograft rejection by a novel retinoic acid receptor-alpha-selective agonist. Int Immunol. 2004; 16(5):665-73. DOI: 10.1093/intimm/dxh066. View

15.

Beard R, Duong T, Teng M, Klein E, Standevan A, Chandraratna R . Synthesis and biological activity of retinoic acid receptor-alpha specific amides. Bioorg Med Chem Lett. 2002; 12(21):3145-8. DOI: 10.1016/s0960-894x(02)00647-9. View

16.

Cheeseright T, Mackey M, Melville J, Vinter J . FieldScreen: virtual screening using molecular fields. Application to the DUD data set. J Chem Inf Model. 2008; 48(11):2108-17. DOI: 10.1021/ci800110p. View

17.

Vinter J . Extended electron distributions applied to the molecular mechanics of some intermolecular interactions. J Comput Aided Mol Des. 1994; 8(6):653-68. DOI: 10.1007/BF00124013. View

18.

Arafa H, Elmazar M, Hamada F, Reichert U, Shroot B, Nau H . Selective agonists of retinoic acid receptors: comparative toxicokinetics and embryonic exposure. Arch Toxicol. 2000; 73(10-11):547-56. DOI: 10.1007/s002040050007. View