title: Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY-876.
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.
authors.affiliation: Bayer AG, Drug Discovery, 13353, Berlin, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Siebeneicher
authors.affiliation: Bayer AG, Drug Discovery, 13353, Berlin, Germany.
authors.forename: Arwed
authors.initials: A
authors.lastname: Cleve
authors.affiliation: Bayer AG, Drug Discovery, 13353, Berlin, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Rehwinkel
authors.affiliation: Bayer AG, Drug Discovery, 13353, Berlin, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Neuhaus
authors.affiliation: Bayer AG, Drug Discovery, 42096, Wuppertal, Germany.
authors.forename: Iring
authors.initials: I
authors.lastname: Heisler
authors.affiliation: Bayer AG, Drug Discovery, 42096, Wuppertal, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.affiliation: Bayer AG, Drug Discovery, 13353, Berlin, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bauser
authors.affiliation: Bayer AG, Drug Discovery, 13353, Berlin, Germany. bernd.buchmann@bayer.com.
authors.forename: Bernd
authors.initials: B
authors.lastname: Buchmann
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D015394:Molecular Structure; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000620175:BAY-876; D051272:Glucose Transporter Type 1; D011720:Pyrazoles; D011804:Quinolines; C495677:SLC2A1 protein, human
keywords: GLUT1 inhibitors; Warburg effect; medicinal chemistry; quinoline carboxamides; structure-activity relationships