title: Discovery of pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists.
abstract: We designed and synthesized a novel series of phenylamino- and phenoxy-substituted pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists. SAR studies indicated that electron-withdrawing substituents on the phenyl ring are important for potency and full efficacy. Compound 26 combined good potency with a promising pharmacokinetic profile in mice, and lowered the glucose excursion in mice in an oral glucose-tolerance test.
authors.affiliation: Department of Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. Electronic address: paul.gillespie@roche.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Gillespie
authors.affiliation: Department of Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Goodnow
authors.affiliation: TCG Lifesciences Limited, Salt Lake Electronic Complex, Block BN, Plot 7, Sector V, Kolkata 700 091, India.
authors.forename: Goutam
authors.initials: G
authors.lastname: Saha
authors.affiliation: TCG Lifesciences Limited, Salt Lake Electronic Complex, Block BN, Plot 7, Sector V, Kolkata 700 091, India.
authors.forename: Gopal
authors.initials: G
authors.lastname: Bose
authors.affiliation: TCG Lifesciences Limited, Salt Lake Electronic Complex, Block BN, Plot 7, Sector V, Kolkata 700 091, India.
authors.forename: Kakali
authors.initials: K
authors.lastname: Moulik
authors.affiliation: Metabolic and Vascular Diseases, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Zwingelstein
authors.affiliation: Metabolic and Vascular Diseases, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Myers
authors.affiliation: Metabolic and Vascular Diseases, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Conde-Knape
authors.affiliation: Department of Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Sherrie
authors.initials: S
authors.lastname: Pietranico-Cole
authors.affiliation: Department of Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Sung-Sau
authors.initials: SS
authors.lastname: So
mesh_terms: D000818:Animals; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C516207:Gpr119 protein, mouse; D011720:Pyrazoles; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; C030986:pyrimidine
keywords: Agonist; GPCR; GPR119; Oral glucose tolerance test; Type 2 diabetes