Potent blockers of the monocarboxylate transporter MCT1: novel immunomodulatory compounds.
A novel series of potent blockers of the monocarboxylate transporter, MCT1, is disclosed. From very potent but lipophilic lead compounds, systematic changes to all parts of the molecule, targeting reduction in log D, afforded compounds with significantly improved overall properties. These compounds show potent immunomodulatory activity.
Guile
S D
SD
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK. simon.guile@astrazeneca.com
Bantick
J R
JR
Cheshire
D R
DR
Cooper
M E
ME
Davis
A M
AM
Donald
D K
DK
Evans
R
R
Eyssade
C
C
Ferguson
D D
DD
Hill
S
S
Hutchinson
R
R
Ingall
A H
AH
Kingston
L P
LP
Martin
I
I
Martin
B P
BP
Mohammed
R T
RT
Murray
C
C
Perry
M W D
MW
Reynolds
R H
RH
Thorne
P V
PV
Wilkinson
D J
DJ
Withnall
J
J
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000276:immunology / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D006086:Graft vs Host Disease / Q000276:immunology; D006564:Herpesviridae / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology*; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000099233:Monocarboxylate Transport Protein 1
D001189:Aryl Hydrocarbon Hydroxylases; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D007155:Immunologic Factors; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C450260:CYP2C9 protein, human; C104464:CYP3A protein, human