Nanomolar potency and metabolically stable inhibitors of kidney urea transporter UT-B.
Urea transporters, which include UT-B in kidney microvessels, are potential targets for development of drugs with a novel diuretic ('urearetic') mechanism. We recently identified, by high-throughput screening, a triazolothienopyrimidine UT-B inhibitor, 1, that selectively and reversibly inhibited urea transport with IC(50) = 25.1 nM and reduced urinary concentration in mice ( Yao et al. J. Am. Soc. Nephrol. , in press ). Here, we analyzed 273 commercially available analogues of 1 to establish a structure-activity series and synthesized a targeted library of 11 analogues to identify potent, metabolically stable UT-B inhibitors. The best compound, {3-[4-(1,1-difluoroethyl)benzenesulfonyl]thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}thiophen-2-ylmethylamine, 3k, had IC(50) of 23 and 15 nM for inhibition of urea transport by mouse and human UT-B, respectively, and ∼40-fold improved in vitro metabolic stability compared to 1. In mice, 3k accumulated in kidney and urine and reduced maximum urinary concentration. Triazolothienopyrimidines may be useful for therapy of diuretic-refractory edema in heart and liver failure.
Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California 94132-4136, United States. marc@sfsu.edu
Marc O
MO
Anderson
Jicheng
J
Zhang
Yan
Y
Liu
Chenjuan
C
Yao
Puay-Wah
PW
Phuan
A S
AS
Verkman
D000818:Animals; D015195:Drug Design; D004355:Drug Stability; D020128:Inhibitory Concentration 50; D007668:Kidney; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000096982:Urea Transporters
D026901:Membrane Transport Proteins; D011743:Pyrimidines; D000096982:Urea Transporters