Synthesis and Pharmacological Characterization of 2-(2,6-Dichlorophenyl)-1((1S,3R)-5-(3-hydroxy-3-methylbutyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (LY3154207), a Potent, Subtype Selective, and Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor

被引：42

作者：

Hao, Junliang ^{[1
]}

Beck, James P. ^{[1
]}

Schaus, John M. ^{[1
]}

Krushinski, Joseph H. ^{[1
]}

Chen, Qi ^{[1
]}

Beadle, Christopher D. ^{[1
]}

Vidal, Paloma ^{[1
]}

Reinhard, Matthew R. ^{[1
]}

Dressman, Bruce A. ^{[1
]}

Massey, Steven M. ^{[1
]}

Boulet, Serge L. ^{[1
]}

Cohen, Michael P. ^{[1
]}

Watson, Brian M. ^{[1
]}

Tupper, David ^{[1
]}

Gardiner, Kevin M. ^{[1
]}

Myers, Jason ^{[1
]}

Johansson, Anette M. ^{[1
]}

Richardson, Jeffery ^{[1
]}

Richards, Daniel S. ^{[6
]}

Hembre, Erik J. ^{[1
]}

Remick, David M. ^{[2
]}

Coates, David A. ^{[2
]}

Bhardwaj, Rajni M. ^{[2
]}

Diseroad, Benjamin A. ^{[2
]}

Bender, David ^{[2
]}

Stephenson, Greg ^{[2
]}

Wolfangel, Craig D. ^{[2
]}

Diaz, Nuria ^{[2
]}

Getman, Brian G. ^{[3
]}

Wang, Xu-shan ^{[3
]}

Heinz, Beverly A. ^{[3
]}

Cramer, Jeff W. ^{[4
]}

Zhou, Xin ^{[4
]}

Maren, Deanna L. ^{[5
]}

Falcone, Julie F. ^{[5
]}

Wright, Rebecca A. ^{[5
]}

Mitchell, Stephen N. ^{[5
]}

Carter, Guy ^{[5
]}

Yang, Charles R. ^{[5
]}

Bruns, Robert F. ^{[1
]}

Svensson, Kjell A. ^{[5
]}

机构：

[1] Eli Lilly & Co, Lilly Res Labs, Discovery Chem Res & Technol, Indianapolis, IN 46285 USA

[2] Eli Lilly & Co, Lilly Res Labs, Small Mol Drug Dev, Indianapolis, IN 46285 USA

[3] Eli Lilly & Co, Lilly Res Labs, Quantitat Biol, Indianapolis, IN 46285 USA

[4] Eli Lilly & Co, Lilly Res Labs, Drug Disposit, Indianapolis, IN 46285 USA

[5] Eli Lilly & Co, Lilly Res Labs, Neurosci Discovery, Indianapolis, IN 46285 USA

[6] AMRI UK Ltd, Sunninghill Rd, Windlesham GU20 6PH, Surrey, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 19期

关键词：

PROTEIN-COUPLED RECEPTORS; D-1; RECEPTOR; PHARMACEUTICAL COCRYSTALS; ACETYLCHOLINE-RELEASE; AGONIST DIHYDREXIDINE; COGNITIVE DEFICITS; IN-VITRO; EXPRESSION; DISCOVERY; LIGANDS;

D O I：

10.1021/acs.jmedchem.9b01234

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.

引用

页码：8711 / 8732

页数：22

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