Transaminases Provide Key Chiral Building Blocks for the Synthesis of Selective M1/M4 Agonists

被引：1

作者：

Thomson, Christopher G. ^{[1
,2
]}

Boss, Kelly ^{[1
,3
]}

Calhoun, Amy ^{[1
]}

Fridrich, Cary ^{[1
,4
]}

Gardinier, Kevin M. ^{[1
,5
]}

Hall, Edward C. ^{[1
]}

Jendza, Keith ^{[1
]}

Kirman, Louise ^{[1
]}

Labbe-Giguere, Nancy ^{[1
]}

Laumen, Kurt ^{[6
]}

Qian, Ming ^{[1
]}

Sanyal, Sanjit ^{[1
,7
]}

Shultz, Michael D. ^{[1
]}

Snajdrova, Radka ^{[6
]}

Tan, Kian ^{[1
]}

Wang, Kate Yaping ^{[1
]}

Yang, Fan ^{[1
]}

Gao, Feng ^{[8
]}

Hong, Tao ^{[8
]}

Dale, Elena ^{[9
,10
]}

Kuzmiski, Brent ^{[9
]}

Ortuno, Danny ^{[9
,12
]}

Palacios, Daniel S. ^{[11
]}

机构：

[1] Global Discovery Chem, Novartis Biomed Res, Cambridge, MA 02139 USA

[2] Pharmaron UK Ltd, Innovat Pk,West Cl,Hertford Rd, Hoddesdon EN11 9FH, England

[3] Vertex Pharmaceut, 50 Northern Ave, Boston, MA 02210 USA

[4] Relay Therapeut, 399 Binney St,Suite 2, Cambridge, MA 02142 USA

[5] Karuna Therapeut, 99 High St Floor 26, Boston, MA 02110 USA

[6] Novartis Inst BioMed Res, Global Discovery Chem, CH-4002 Basel, Switzerland

[7] Theseus Pharmaceut, 314 Main St Suite 04-200, Cambridge, MA 02142 USA

[8] Suzhou Novartis Tech Dev Co Ltd, Chem & Analyt Dev, Changshu 215537, Jiangsu, Peoples R China

[9] Neurosci Dis Area, Novartis Biomed Res, Cambridge, MA 02139 USA

[10] Eisai & Co Ltd, 35 Cambridge Pk Dr, Cambridge, MA 02140 USA

[11] Novartis Inst Biomed Res, Global Discovery Chem, San Diego, CA 92121 USA

[12] Octet Med, 13400 Sabre Springs Pkwy, San Diego, CA 92128 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2023年 / 14卷 / 12期

关键词：

selective CHRM4 agonist; biocatalysis; asymmetricsynthesis; muscarinic receptors; bifunctional aminebuilding blocks; aminotransferase; MUSCARINIC RECEPTOR AGONIST; M-1; XANOMELINE; DISCOVERY; DERIVATIVES; POTENT;

D O I：

10.1021/acsmedchemlett.3c00331

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We have developed a chiral route toward the synthesis of muscarinic M4 agonists that was enabled by the biocatalytic synthesis of the key spirocyclic diamine building blocks 10 and 12. Using these bifunctional compounds we were able to optimize a synthetic sequence toward a collection of advanced intermediates for further elaboration. These advanced intermediates were then used as starting points for early medicinal chemistry and the identification of selective M1/M4 agonists.

引用

页码：1692 / 1699

页数：8

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