Isolation, Structural Identification, Synthesis, and Pharmacological Profiling of 1,2-trans-Dihydro-1,2-diol Metabolites of the Utrophin Modulator Ezutromid

被引：9

作者：

Chatzopoulou, Maria ^{[1
]}

Claridge, Tim D. W. ^{[1
]}

Davies, Kay E. ^{[2
]}

Davies, Stephen G. ^{[1
]}

Elsey, David J. ^{[3
]}

Emer, Enrico ^{[1
]}

Fletcher, Ai M. ^{[1
]}

Harriman, Shawn ^{[4
]}

Robinson, Neil ^{[5
]}

Rowley, Jessica A. ^{[1
]}

Russell, Angela J. ^{[1
,6
]}

Tinsley, Jonathon M. ^{[3
]}

Weaver, Richard ^{[7
]}

Wilkinson, Isabel V. L. ^{[1
]}

Willis, Nicky J. ^{[1
]}

Wilson, Francis X. ^{[3
]}

Wynne, Graham M. ^{[1
]}

机构：

[1] Univ Oxford, Dept Chem, Chem Res Lab, Mansfield Rd, Oxford OX1 3TA, England

[2] Univ Oxford, MDUK Oxford Neuromuscular Ctr, Dept Physiol Anat & Genet, Oxford OX1 3PT, England

[3] Summit Therapeut Plc, 136a Eastern Ave,Milton Pk, Abingdon OX14 4SB, Oxon, England

[4] Summit Therapeut Plc, One Broadway,14th Floor, Cambridge, MA 02142 USA

[5] SHB Enterprises Ltd, 55 Stn Rd, Beaconsfield HP19 1QL, England

[6] Univ Oxford, Dept Pharmacol, Mansfield Rd, Oxford OX1 3PQ, England

[7] BioC Nottingham, XenoGesis Ltd, Pennyfoot St, Nottingham NG1 1GF, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 05期

基金：

英国医学研究理事会; 英国工程与自然科学研究理事会;

关键词：

MUSCULAR-DYSTROPHY; SUBSTITUTED NAPHTHALENES; ESCHERICHIA-COLI; CRTH2; ANTAGONIST; OXIDATION; GENE; STEREOCHEMISTRY; DISPOSITION; EXPRESSION; TOLUENE;

D O I：

10.1021/acs.jmedchem.9b01547

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

5-(Ethylsulfonyl)-2-( naphthalen-2-yl) benzo[d]-oxazole (ezutromid, 1) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisomeric 1,2-dihydronaphthalene-1,2-diols, DHD1 and DHD3, as the major metabolites after oral administration in humans and rodents. In many patients, plasma levels of the DHD metabolites were found to exceed those of ezutromid. Herein, we describe the structural elucidation of the main metabolites of ezutromid, the regio- and relative stereochemical assignments of DHD1 and DHD3, their de novo chemical synthesis, and their production in systems in vitro. We further elucidate the likely metabolic pathway and CYP isoforms responsible for DHD1 and DHD3 production and characterize their physicochemical, ADME, and pharmacological properties and their preliminary toxicological profiles.

引用

页码：2547 / 2556

页数：10

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