Free fatty acid receptor 1 (FFA1/GPR40) agonists: mesylpropoxy appendage lowers lipophilicity and improves ADME properties.
FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on 5. The appendage significantly lowers lipophilicity and improves metabolic stability while preserving potency, resulting in discovery of the potent FFA1 agonist 13.
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
Elisabeth
E
Christiansen
Maria E
ME
Due-Hansen
Christian
C
Urban
Manuel
M
Grundmann
Ralf
R
Schröder
Brian D
BD
Hudson
Graeme
G
Milligan
Michael A
MA
Cawthorne
Evi
E
Kostenis
Matthias U
MU
Kassack
Trond
T
Ulven
D000042:Absorption; D001554:Benzene / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
C473034:FFAR1 protein, human; D043562:Receptors, G-Protein-Coupled; D001554:Benzene