title: Discovery of triazolopyrimidine-based PDE8B inhibitors: exceptionally ligand-efficient and lipophilic ligand-efficient compounds for the treatment of diabetes.
abstract: PDE8B is a cAMP-specific isoform of the broader class of phosphodiesterases (PDEs). As no selective PDE8B inhibitors had been reported, a high throughput screen was run with the goal of identifying selective tools for exploring the potential therapeutic utility of PDE8B inhibition. Of the numerous hits, one was particularly attractive since it was amenable to rapid deconstruction leading to inhibitors with very high ligand efficiency (LE) and lipophilic ligand efficiency (LLE). These triazolopyrimidines were optimized for potency, selectivity and ADME properties ultimately leading to compound 42. This compound was highly potent and selective with good bioavailability and advanced into pre-clinical development.
authors.affiliation: Pfizer Global Research & Development-Groton Laboratories, Groton, CT 06340, USA. mike_deninno@sd.vrtx.com
authors.forename: Michael P
authors.initials: MP
authors.lastname: DeNinno
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wright
authors.forename: John B
authors.initials: JB
authors.lastname: Etienne
authors.forename: Thanh V
authors.initials: TV
authors.lastname: Olson
authors.forename: Benjamin N
authors.initials: BN
authors.lastname: Rocke
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Corbett
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Kung
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: DiRico
authors.forename: Kim M
authors.initials: KM
authors.lastname: Andrews
authors.forename: Michele L
authors.initials: ML
authors.lastname: Millham
authors.forename: Janice C
authors.initials: JC
authors.lastname: Parker
authors.forename: William
authors.initials: W
authors.lastname: Esler
authors.forename: Maria
authors.initials: M
authors.lastname: van Volkenburg
authors.forename: David D
authors.initials: DD
authors.lastname: Boyer
authors.forename: Karen L
authors.initials: KL
authors.lastname: Houseknecht
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Doran
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000201:enzymology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D008024:Ligands; D011743:Pyrimidines; D014230:Triazoles; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C468781:PDE8B protein, human