title: Optimization of monocarboxylate transporter 1 blockers through analysis and modulation of atropisomer interconversion properties.
abstract: We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK. simon.guile@astrazeneca.com
authors.forename: Simon D
authors.initials: SD
authors.lastname: Guile
authors.forename: John R
authors.initials: JR
authors.lastname: Bantick
authors.forename: Martin E
authors.initials: ME
authors.lastname: Cooper
authors.forename: David K
authors.initials: DK
authors.lastname: Donald
authors.forename: Christine
authors.initials: C
authors.lastname: Eyssade
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Ingall
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.forename: Barrie P
authors.initials: BP
authors.lastname: Martin
authors.forename: Rukhsana T
authors.initials: RT
authors.lastname: Mohammed
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Potter
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Reynolds
authors.forename: Stephen A
authors.initials: SA
authors.lastname: St-Gallay
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Wright
mesh_terms: D007536:Isomerism; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000737:chemistry; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D007555:Isoxazoles; D027501:Monocarboxylic Acid Transporters; D009281:Naphthalenes; D011759:Pyrrolidines; D011804:Quinolines; D027981:Symporters; D053778:Thiazolidines; D000099233:Monocarboxylate Transport Protein 1