Optimization of monocarboxylate transporter 1 blockers through analysis and modulation of atropisomer interconversion properties.
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.
Guile
Simon D
SD
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK. simon.guile@astrazeneca.com
Bantick
John R
JR
Cooper
Martin E
ME
Donald
David K
DK
Eyssade
Christine
C
Ingall
Anthony H
AH
Lewis
Richard J
RJ
Martin
Barrie P
BP
Mohammed
Rukhsana T
RT
Potter
Timothy J
TJ
Reynolds
Rachel H
RH
St-Gallay
Stephen A
SA
Wright
Andrew D
AD
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
D007555:Isoxazoles; D027501:Monocarboxylic Acid Transporters; D009281:Naphthalenes; D011759:Pyrrolidines; D011804:Quinolines; D027981:Symporters; D053778:Thiazolidines; D000099233:Monocarboxylate Transport Protein 1