title: The discovery of a novel series of glucokinase activators based on a pyrazolopyrimidine scaffold.
abstract: Glucokinase is a key enzyme in glucose homeostasis since it phosphorylates glucose to give glucose-6-phosphate, which is the first step in glycolysis. GK activators have been proven to lower blood-glucose, and therefore have potential as treatments for type 2 diabetes. Here the discovery of pyrazolopyrimidine GKAs is reported. An original singleton hit from a high-throughput screen with micromolar levels of potency was optimised to give compounds with nanomolar activities. Key steps in this success were the introduction of an extra side-chain, which increased potency, and changing the linking functionality from a thioether to an ether, which led to improved potency and lipophilic ligand efficiency. This also led to more stable compounds with improved profiles in biological assays.
authors.affiliation: Cardiovascular and Gastrointestinal Innovative Medicines, AstraZeneca, S-431 83 Mölndal, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Bonn
authors.forename: D Mikael
authors.initials: DM
authors.lastname: Brink
authors.forename: Jonas
authors.initials: J
authors.lastname: Fägerhag
authors.forename: Ulrik
authors.initials: U
authors.lastname: Jurva
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Robb
authors.forename: Volker
authors.initials: V
authors.lastname: Schnecke
authors.forename: Anette
authors.initials: A
authors.lastname: Svensson Henriksson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Waring
authors.forename: Christer
authors.initials: C
authors.lastname: Westerlund
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D005941:Glucokinase / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; D005941:Glucokinase