Spirocyclic Scaffolds in Medicinal Chemistry

被引：408

作者：

Hiesinger, Kerstin ^{[1
]}

Dar'in, Dmitry ^{[2
]}

Proschak, Ewgenij ^{[1
]}

Krasavin, Mikhail ^{[2
]}

机构：

[1] Goethe Univ, Inst Pharmaceut Chem, D-60348 Frankfurt, Germany

[2] St Petersburg State Univ, Inst Chem, St Petersburg 199034, Russia

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 01期

基金：

俄罗斯科学基金会;

关键词：

SMALL-MOLECULE INHIBITORS; RECEPTOR ANTAGONISTS; GPR40; AGONISTS; HIGH-AFFINITY; DISCOVERY; POTENT; FENSPIRIDE; OPTIMIZATION; PROLINE; DESIGN;

D O I：

10.1021/acs.jmedchem.0c01473

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest in less planar bioactive compounds has given rise to the development of synthetic methodologies for the preparation of spirocyclic scaffolds. In this Perspective, we summarize the diverse synthetic routes to obtain spirocyclic systems. The impact of spirocycles on potency and selectivity, including the aspect of stereochemistry, is discussed. Furthermore, we examine the changes in physicochemical properties as well as in in vitro and in vivo ADME using selected studies that compare spirocyclic compounds to their nonspirocyclic counterparts. In conclusion, the value of spirocyclic scaffolds in medicinal chemistry is discussed.

引用

页码：150 / 183

页数：34

共 163 条

[1] N-Alkylated aziridines are easily-prepared, potent, specific and cell-permeable covalent inhibitors of human β-glucocerebrosidase [J].

Adams, B. T. ;

Niccoli, S. ;

Chowdhury, M. A. ;

Esarik, A. N. K. ;

Lees, S. J. ;

Rempel, B. P. ;

Phenix, C. P. .

CHEMICAL COMMUNICATIONS, 2015, 51 (57) :11390-11393

[2] Apalutamide: First Global Approval [J].

Al-Salama, Zaina T. .

DRUGS, 2018, 78 (06) :699-705

[3]

Alcaraz L., 2011, Compounds-801, Patent No. [WO2011012896A2, 2011012896]

[4] Fragment-Based Discovery of Novel Potent Sepiapterin Reductase Inhibitors [J].

Alen, Jo ;

Schade, Markus ;

Wagener, Markus ;

Christian, Frank ;

Nordhoff, Sonja ;

Merla, Beatrix ;

Dunkern, Torsten R. ;

Bahrenberg, Gregor ;

Ratcliffe, Paul .

JOURNAL OF MEDICINAL CHEMISTRY, 2019, 62 (13) :6391-6397

[5]

Ang S. H., 2009, Patent No. [WO2009132921A1, 2009132921A1]

[6] Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality [J].

Arkin, Michelle R. ;

Tang, Yinyan ;

Wells, James A. .

CHEMISTRY & BIOLOGY, 2014, 21 (09) :1102-1114

[7] Process Development of a Suzuki Reaction Used in the Manufacture of Lanabecestat [J].

Ashworth, Ian W. ;

Campbell, Andrew D. ;

Cherryman, Janette H. ;

Clark, Jemma ;

Crampton, Alex ;

Eden-Rump, Edward G. B. ;

Evans, Matthew ;

Jones, Martin F. ;

McKeever-Abbas, Sahar ;

Meadows, Rebecca E. ;

Skilling, Kathryn ;

Whittaker, David T. E. ;

Woodward, Robert L. ;

Inglesby, Phillip A. .

ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2018, 22 (12) :1801-1808

[8] Recent progress in sodium channel modulators for pain [J].

Bagal, Sharan K. ;

Chapman, Mark L. ;

Marron, Brian E. ;

Prime, Rebecca ;

Storer, R. Ian ;

Swain, Nigel A. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2014, 24 (16) :3690-3699

[9] Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors [J].

Bagdanoff, Jeffrey T. ;

Chen, Zhouliang ;

Acker, Michael ;

Chen, Ying-Nan ;

Chan, Homan ;

Dore, Michael ;

Firestone, Brant ;

Fodor, Michelle ;

Fortanet, Jorge ;

Hentemann, Murphy ;

Kato, Mitsunori ;

Koenig, Robert ;

LaBonte, Laura R. ;

Liu, Shumei ;

Mohseni, Movarid ;

Ntaganda, Rukundo ;

Sarver, Patrick ;

Smith, Troy ;

Sendzik, Martin ;

Stams, Travis ;

Spence, Stan ;

Towler, Christopher ;

Wang, Hongyun ;

Wang, Ping ;

Williams, Sarah L. ;

LaMarche, Matthew J. .

JOURNAL OF MEDICINAL CHEMISTRY, 2019, 62 (04) :1781-1792

[10] Advances in Spirocyclic Hybrids: Chemistry and Medicinal Actions [J].

Benadallah, Mohammed ;

Talhi, Oualid ;

Nouali, Fatiha ;

Choukchou-Braham, Nouredine ;

Bachari, Khaldoun ;

Silva, Artur M. S. .

CURRENT MEDICINAL CHEMISTRY, 2018, 25 (31) :3748-3767

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