Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity

被引：58

作者：

Graceffa, Russell F. ^{[1
]}

Boezio, Alessandro A. ^{[1
]}

Able, Jessica ^{[6
]}

Altmann, Steven ^{[4
,9
]}

Berry, Loren M. ^{[3
]}

Boezio, Christiane ^{[1
]}

Butler, John R. ^{[1
]}

Chu-Moyer, Margaret ^{[1
]}

Cooke, Melanie ^{[5
]}

DiMauro, Erin F. ^{[1
,10
]}

Dineen, Thomas A. ^{[1
,7
]}

Bojic, Elma Feric ^{[4
,11
]}

Foti, Robert S. ^{[3
]}

Fremeau, Robert T., Jr. ^{[4
,14
]}

Guzman-Perez, Angel ^{[1
]}

Gao, Hua ^{[2
,11
]}

Gunaydin, Hakan ^{[2
]}

Huang, Hongbing ^{[1
,12
]}

Huang, Liyue ^{[3
]}

Ilch, Christopher ^{[4
]}

Jarosh, Michael ^{[4
]}

Kornecook, Thomas ^{[6
]}

Kreiman, Charles R. ^{[1
]}

La, Daniel S. ^{[1
]}

Ligutti, Joseph ^{[6
]}

Milgram, Benjamin C. ^{[1
]}

Lin, Min-Hwa Jasmine ^{[3
]}

Marx, Isaac E. ^{[1
,8
]}

Nguyen, Hanh N. ^{[1
,13
]}

Peterson, Emily A. ^{[1
]}

Rescourio, Gwen ^{[1
]}

Roberts, John ^{[3
]}

Schenkel, Laurie ^{[1
]}

Shimanovich, Roman

Sparling, Brian A. ^{[1
]}

Stellwagen, John ^{[1
]}

Taborn, Kristin ^{[4
]}

Vaida, Karina R. ^{[1
]}

Wang, Jean ^{[4
]}

Yeoman, John ^{[1
]}

Yu, Violeta ^{[4
]}

Zhu, Dawn ^{[4
]}

Moyer, Bryan D. ^{[6
]}

Weiss, Matthew M. ^{[1
]}

机构：

[1] Amgen Inc, Dept Therapeut Discovery, 360 Binney St, Cambridge, MA 02142 USA

[2] Amgen Inc, Dept Mol Engn, 360 Binney St, Cambridge, MA 02142 USA

[3] Amgen Inc, Dept Pharmacokinet & Drug Metab, 360 Binney St, Cambridge, MA 02142 USA

[4] Amgen Inc, Dept Neurosci, 360 Binney St, Cambridge, MA 02142 USA

[5] Amgen Inc, Dept Pharmaceut, 360 Binney St, Cambridge, MA 02142 USA

[6] Amgen Inc, Dept Neurosci, 1 Amgen Ctr Dr, Thousand Oaks, CA 91320 USA

[7] Novartis Inst Biomed Res, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[8] Biogen, 225 Binney St, Cambridge, MA 02142 USA

[9] Sanofi Genzyme, 500 Kendall Sq, Cambridge, MA 02142 USA

[10] Int Burch Univ, Fac Engn & Informat Technol, Dept Genent & Bioengn, Sarajevo 71000, Bosnia & Herceg

[11] Merck Res Labs, 33 Ave Louis Pasteur, Boston, MA 02115 USA

[12] Baylor Coll Med, Ctr Drug Discovery, Dept Pathol & Immunol, 1 Baylor Pl, Houston, TX 77030 USA

[13] Blinkbio, 1200 South Pine Isl Rd, Plantation, FL 33324 USA

[14] NeuroRx Consulting, 854 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 14期

关键词：

EXTREME PAIN DISORDER; MOLECULAR-MECHANISM; DRUG DISCOVERY; MUTATIONS; ERYTHROMELALGIA; INACTIVATION; ANTAGONISTS; CHALLENGE; DEFECTS; VITRO;

D O I：

10.1021/acs.jmedchem.6b01850

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Because of its strong genetic validation, Na(V)1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as Na(V)1.7 inhibitors that demonstrate high levels of selectivity over other Na-V isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation. WO 2014201206, 2014] of Na(V)1.7, which demonstrate nanomolar inhibition of Na(V)1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound 39 (AM-0466) demonstrated robust pharmacodynarnic activity in a Na(V)1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of pain without any confounding effect in open-field activity.

引用

页码：5990 / 6017

页数：28

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