title: 1,1-Difluoroethyl-substituted triazolothienopyrimidines as inhibitors of a human urea transport protein (UT-B): new analogs and binding model.
abstract: The kidney urea transport protein UT-B is an attractive target for the development of small-molecule inhibitors with a novel diuretic ('urearetic') action. Previously, two compounds in the triazolothienopyrimidine scaffold (1a and 1c) were reported as UT-B inhibitors. Compound 1c incorporates a 1,1-difluoroethyl group, which affords improved microsomal stability when compared to the corresponding ethyl-substituted compound 1a. Here, a small focused library (4a-4f) was developed around lead inhibitor 1c to investigate the requirement of an amidine-linked thiophene in the inhibitor scaffold. Two compounds (4a and 4b) with nanomolar inhibitory potency (IC50≈40 nM) were synthesized. Computational docking of lead structure 1c and 4a-4f into a homology model of the UT-B cytoplasmic surface suggested binding with the core heterocycle buried deep into the hydrophobic pore region of the protein.
authors.affiliation: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132-4236, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: C
authors.initials: C
authors.lastname: Esteva-Font
authors.forename: C
authors.initials: C
authors.lastname: Yao
authors.forename: P W
authors.initials: PW
authors.lastname: Phuan
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
authors.forename: M O
authors.initials: MO
authors.lastname: Anderson
mesh_terms: D001665:Binding Sites; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000096982:Urea Transporters
chemical_list: D005461:Fluorine; D026901:Membrane Transport Proteins; D011743:Pyrimidines; D000096982:Urea Transporters