title: 2,3-Disubstituted acrylamides as potent glucokinase activators.
abstract: 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.
authors.affiliation: Department of Discovery Chemistry, Roche Research Center, 340 Kingsland Street, Nutley, NJ 07110, USA. achyutharao.sidduri@roche.com
authors.forename: Achyutharao
authors.initials: A
authors.lastname: Sidduri
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Grimsby
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Corbett
authors.forename: Ramakanth
authors.initials: R
authors.lastname: Sarabu
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Grippo
authors.forename: Jianping
authors.initials: J
authors.lastname: Lou
authors.forename: Robert F
authors.initials: RF
authors.lastname: Kester
authors.forename: Mark
authors.initials: M
authors.lastname: Dvorozniak
authors.forename: Linda
authors.initials: L
authors.lastname: Marcus
authors.forename: Cheryl
authors.initials: C
authors.lastname: Spence
authors.forename: Jagdish K
authors.initials: JK
authors.lastname: Racha
authors.forename: David J
authors.initials: DJ
authors.lastname: Moore
mesh_terms: 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
chemical_list: D000178:Acrylamides; D044482:Benzeneacetamides; D007004:Hypoglycemic Agents; D013450:Sulfones; D005941:Glucokinase