Format

Send to

Choose Destination
ChemMedChem. 2016 Oct 19;11(20):2261-2271. doi: 10.1002/cmdc.201600276. Epub 2016 Aug 23.

Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY-876.

Author information

1
Bayer AG, Drug Discovery, 13353, Berlin, Germany.
2
Bayer AG, Drug Discovery, 42096, Wuppertal, Germany.
3
Bayer AG, Drug Discovery, 13353, Berlin, Germany. bernd.buchmann@bayer.com.

Abstract

Despite the long-known fact that the facilitative glucose transporter GLUT1 is one of the key players safeguarding the increase in glucose consumption of many tumor entities even under conditions of normal oxygen supply (known as the Warburg effect), only few endeavors have been undertaken to find a GLUT1-selective small-molecule inhibitor. Because other transporters of the GLUT1 family are involved in crucial processes, these transporters should not be addressed by such an inhibitor. A high-throughput screen against a library of ∼3 million compounds was performed to find a small molecule with this challenging potency and selectivity profile. The N-(1H-pyrazol-4-yl)quinoline-4-carboxamides were identified as an excellent starting point for further compound optimization. After extensive structure-activity relationship explorations, single-digit nanomolar inhibitors with a selectivity factor of >100 against GLUT2, GLUT3, and GLUT4 were obtained. The most promising compound, BAY-876 [N4 -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dicarboxamide], showed good metabolic stability in vitro and high oral bioavailability in vivo.

KEYWORDS:

GLUT1 inhibitors; Warburg effect; medicinal chemistry; quinoline carboxamides; structure-activity relationships

PMID:
27552707
PMCID:
PMC5095872
DOI:
10.1002/cmdc.201600276
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center