2,3-Disubstituted acrylamides as potent glucokinase activators.
The phenylacetamide 1 represents the archtypical glucokinase activator (GKA) in which only the R-isomer is active. In order to probe whether the chiral center could be replaced, we prepared a series of olefins 2 and show in the present work that these compounds represent a new class of GKAs. Surprisingly, the SAR of the new series paralleled that of the saturated derivatives with the exception that there was greater tolerance for larger alkyl and cycloalkyl groups at R(2) region in comparison to the phenylacetamides. In normal Wistar rats, the 2,3-disubstituted acrylamide analog 10 was well absorbed and demonstrated robust glucose lowering effects.
Sidduri
Achyutharao
A
Department of Discovery Chemistry, Roche Research Center, 340 Kingsland Street, Nutley, NJ 07110, USA. achyutharao.sidduri@roche.com
Grimsby
Joseph S
JS
Corbett
Wendy L
WL
Sarabu
Ramakanth
R
Grippo
Joseph F
JF
Lou
Jianping
J
Kester
Robert F
RF
Dvorozniak
Mark
M
Marcus
Linda
L
Spence
Cheryl
C
Racha
Jagdish K
JK
Moore
David J
DJ
D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D044482:Benzeneacetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D005941:Glucokinase / Q000737:chemistry* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D000178:Acrylamides; D044482:Benzeneacetamides; D007004:Hypoglycemic Agents; D013450:Sulfones; D005941:Glucokinase