- Discovery of Orally Bioavailable Selective Inhibitors of the Sodium-Phosphate Cotransporter NaPi2a (SLC34A1)
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Sodium-phosphate cotransporter 2a, or NaPi2a (SLC34A1), is a solute-carrier (SLC) transporter located in the kidney proximal tubule that reabsorbs glomerular-filtered phosphate. Inhibition of NaPi2a may enhance urinary phosphate excretion and correct maladaptive mineral and hormonal derangements associated with increased cardiovascular risk in chronic kidney disease-mineral and bone disorder (CKD-MBD). To date, only nonselective NaPi inhibitors have been described. Herein, we detail the discovery of the first series of selective NaPi2a inhibitors, resulting from optimization of a high-throughput screening hit. The oral PK profile of inhibitor PF-06869206 (6f) in rodents allows for the exploration of the pharmacology of selective NaPi2a inhibition.
- Filipski, Kevin J.,Sammons, Matthew F.,Bhattacharya, Samit K.,Panteleev, Jane,Brown, Janice A.,Loria, Paula M.,Boehm, Markus,Smith, Aaron C.,Shavnya, Andre,Conn, Edward L.,Song, Kun,Weng, Yan,Facemire, Carie,Jüppner, Harald,Clerin, Valerie
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supporting information
p. 440 - 445
(2018/05/23)
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- BICYCLIC COMPOUNDS HAVING ANTIMITOTIC AND/OR ANTITUMOR ACTIVITY AND METHODS OF USE THEREOF
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The present invention provides bicyclic compounds, pharmaceutically acceptable salts, prodrugs, solvates, and hydrates thereof, having antimitotic activity, anti-multidrug resistance activity, such as for example P-glycoprotein inhibition, and antitumor a
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Page/Page column 13
(2010/02/17)
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- Fused ring compound and use thereof
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The present invention provides a compound represented by the formula: wherein the symbols are as described in the specification, or a salt thereof, which is useful for preventing/treating eicosanoid-associated diseases such as atherosclerosis, diabetes, obesity, atherothrombosis, asthma, fever, pain, cancer, rheumatism, osteoarthritis and atopic dermatitis, and which has an excellent pharmacological action, physicochemical properties, etc.
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Page/Page column 36-37
(2010/08/07)
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- Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors
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We designed and synthesized a classical antifolate N-{4-[(2-amino-6-methyl- 4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl}-L-glutamic acid 4 and 11 nonclassical analogues 5-15 as potential dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. The key intermediate in the synthesis was N-(4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-2,2- dimethylpropanamide, 29, to which various 5-benzyl substituents were attached. For the classical analogue 4, the ester obtained from the N-benzylation reaction was deprotected and coupled with diethyl L-glutamate followed by saponification. Compound 4 was a potent dual inhibitor of human TS (IC 50 = 46 nM, about 206-fold more potent than pemetrexed) and DHFR (IC50 = 120 nM, about 55-fold more potent than pemetrexed). The nonclassical analogues were marginal inhibitors of human TS, but four analogues showed potent T. gondii DHFR inhibition along with >100-fold selectivity compared to human DHFR.
- Gangjee, Aleem,Li, Wei,Yang, Jie,Kisliuk, Roy L.
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