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Synfacts 2021; 17(12): 1314
DOI: 10.1055/s-0041-1737090
DOI: 10.1055/s-0041-1737090
Synthesis of Natural Products and Potential Drugs
Synthesis of BMS-986158
Gavai AV.
*
et al.
Bristol Myers Squibb Company, Princeton, USA
Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.
J. Med. Chem. 2021;
64: 14247-14265
DOI: 10.1021/acs.jmedchem.1c00625.
Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.
J. Med. Chem. 2021;
64: 14247-14265
DOI: 10.1021/acs.jmedchem.1c00625.
Key words
BMS-986158 - Stille coupling - Chan–Lam coupling - copper catalysis - palladium-catalyzed C–H activation - Mitsunobu reaction
Significance
BMS-986158 is an inhibitor of the bromodomain and extra-terminal (BET) family of adaptor proteins that are involved in the transcriptional regulation of key oncogenes. It has entered phase 1/2a clinical trials in patients with advanced cancers and hematologic indications including myelofibrosis.
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Comment
Key steps in the small-scale discovery synthesis of the 5H-pyrido[3,2-b]indole core of BMS-986158 are (1) the copper-catalyzed oxidative coupling of the chloropyridine C with the boronic acid D (Chan–Lam coupling) and (2) the palladium-catalyzed C–H activation reaction E → F.
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Publication History
Article published online:
17 November 2021
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