- Identification of Adenine and Benzimidazole Nucleosides as Potent Human Concentrative Nucleoside Transporter 2 Inhibitors: Potential Treatment for Hyperuricemia and Gout
-
To test the hypothesis that inhibitors of human concentrative nucleoside transporter 2 (hCNT2) suppress increases in serum urate levels derived from dietary purines, we previously identified adenosine derivative 1 as a potent hCNT2 inhibitor (IC50 = 0.64 μM), but further study was hampered due to its poor solubility. Here we describe the results of subsequent research to identify more soluble and more potent hCNT2 inhibitors, leading to the discovery of the benzimidazole nucleoside 22, which is the most potent hCNT2 inhibitor (IC50 = 0.062 μM) reported to date. Compound 22 significantly suppressed the increase in plasma uric acid levels after oral administration of purine nucleosides in rats. Because compound 22 was poorly absorbed orally in rats (F = 0.51%), its pharmacologic action was mostly limited to the gastrointestinal tract. These findings suggest that inhibition of hCNT2 in the gastrointestinal tract can be a promising approach for the treatment of hyperuricemia.
- Tatani, Kazuya,Hiratochi, Masahiro,Kikuchi, Norihiko,Kuramochi, Yu,Watanabe, Shinjiro,Yamauchi, Yuji,Itoh, Fumiaki,Isaji, Masayuki,Shuto, Satoshi
-
supporting information
p. 3719 - 3731
(2016/05/19)
-
- Purinenucleoside derivative modified in 8-position and medical use thereof
-
The present invention provides an 8-modified purinenucleoside derivative which is useful for diseases associated with an abnormality of plasma uric acid level. An 8-modified purinenucleoside derivative represented by the following formula (I), a prodrug thereof or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, is useful for the prevention or treatment of gout, hyperuricemia, urinary lithiasis, hyperuricemic nephropathy or the like. In the formula, n is 1 or 2; RA is a hydrogen atom or a hydroxyl group; R1 is a hydrogen atom, a hydroxyl group, a thiol group, an amino group or a chlorine atom; ring J represents an optionally substituted 2-naphthyl group, or a group represented by the following general formula (II) wherein Y represents a single bond or a connecting group; ring Z represents an optionally substituted aryl group or heteroaryl group or the like; and R2 to R4, P1 and Q represents a halogen atom, a cyano group or the like.
- -
-
Page/Page column 27
(2010/11/28)
-
- Bradykinin B1 antagonists: SAR studies in the 2,3-diaminopyridine series
-
SAR study of the biphenyl region of 2,3-diaminopyridine bradykinin B 1 antagonists was investigated with non-aromatic carbo- and heterocyclic rings. A piperidine ring was found to be a good replacement for the proximal phenyl ring while replacement of the distal phenyl was optimal with a cyclohexyl group leading to a dramatic improvement in affinity for the B 1 receptor.
- Kuduk, Scott D.,Chang, Ronald K.,Ng, Christina,Murphy, Kathy L.,Ransom, Richard W.,Tang, Cuyue,Prueksaritanont, Thomayant,Freidinger, Roger M.,Pettibone, Douglas J.,Bock, Mark G.
-
p. 3925 - 3929
(2007/10/03)
-
- PYRAZOLOPYRIMIDINES AS CYCLIN-DEPENDENT KINASE INHIBITORS
-
In its many embodiments, the present invention provides a novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.
- -
-
-