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. 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

Holger Siebeneicher  1 , Arwed Cleve  1 , Hartmut Rehwinkel  1 , Roland Neuhaus  1 , Iring Heisler  2 , Thomas Müller  2 , Marcus Bauser  1 , Bernd Buchmann  3
Affiliations

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

Holger Siebeneicher et al. ChemMedChem. .

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.

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Figures

Figure 1
Figure 1
Initial SAR beyond HTS hit 1.
Figure 2
Figure 2
Advancing SAR.
Scheme 1
Scheme 1
Reagents and conditions: a) Cs2CO3, MeCN, 60 °C, 92 %; b) Zn, HOAc, EtOH, H2O, 60 °C, 92 %; c) 33 % KOH(aq), pyruvic acid, 40 °C, 85 %; d) 1. SOCl2, reflux, 2. MeOH, reflux, 46 %; e) 7 n NH3 in MeOH, 50 °C, 81 %; f) NaOH(aq), MeOH, RT, 84 %; g) 65, HATU, Et2NiPr, DMSO, RT, 46 %.
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