title: Novel 3,6,7-substituted pyrazolopyrimidines as positive allosteric modulators for the hydroxycarboxylic acid receptor 2 (GPR109A).
abstract: A number of pyrazolopyrimidines were synthesized and tested for their positive allosteric modulation of the HCA(2) receptor (GPR109A). Compound 24, an efficacious and potent agonist and allosteric enhancer of nicotinic acid's action, was the basis for most other compounds. Interestingly, some of the compounds were found to increase the efficacy of the endogenous ligand 3-hydroxybutyrate and enhance its potency almost 10-fold. This suggests that the pyrazolopyrimidines may have therapeutic value when given alone.
authors.affiliation: Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Clara C
authors.initials: CC
authors.lastname: Blad
authors.forename: Jacobus P D
authors.initials: JP
authors.lastname: van Veldhoven
authors.forename: Corné
authors.initials: C
authors.lastname: Klopman
authors.forename: Dieter R
authors.initials: DR
authors.lastname: Wolfram
authors.forename: Johannes
authors.initials: J
authors.lastname: Brussee
authors.forename: J Robert
authors.initials: JR
authors.lastname: Lane
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000494:Allosteric Regulation; D004357:Drug Synergism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D009525:Niacin / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C530636:HCAR2 protein, human; D011720:Pyrazoles; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D009525:Niacin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020155:3-Hydroxybutyric Acid