- Lead optimization of 4-acetylamino-2-(3,5-dimethylpyrazol-1-yl)-6- pyridylpyrimidines as A2A adenosine receptor antagonists for the treatment of Parkinson's disease
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4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA 2A receptor antagonists for the treatment of Parkinson's disease. The 5-methoxy-3-pyridyl derivative 6g (hA2A Ki 2.3 nM, hA1 Ki 190 nM) was orally active at 3 mg/kg in a rat HIC model but exposure was poor in nonrodent species, presumably due to poor aqueous solubility. Follow-on compound 16a (hA2A Ki 0.83 nM, hA1 Ki 130 nM), bearing a 6-(morpholin-4-yl)-2-pyridyl substituent at C-6, had improved solubility and was orally efficacious (3 mg/kg, HIC) but showed time-dependent cytochrome P450 3A4 inhibition, possibly related to morpholine ring metabolism. Compound 16j (hA2A Ki 0.44 nM, hA1 Ki 80 nM), bearing a 6-(4-methoxypiperidin-1-yl)- 2-pyridyl substituent at C-6, was sparingly soluble but had good oral exposure in rodent and nonrodent species, had no cytochrome P450 or human ether-a-go-go related gene channel issues, and was orally efficacious at 1 mg/kg in HIC and at 3 mg/kg for potentiation of L-dopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats.
- Zhang, Xiaohu,Tellew, John E.,Luo, Zhiyong,Moorjani, Manisha,Lin, Emily,Lanier, Marion C.,Chen, Yongsheng,Williams, John P.,Saunders, John,Lechner, Sandra M.,Markison, Stacy,Joswig, Tanya,Petroski, Robert,Piercey, Jaime,Kargo, William,Malany, Siobhan,Santos, Mark,Gross, Raymond S.,Wen, Jenny,Jalali, Kayvon,O'Brien, Zhihong,Stotz, Carol E.,Crespo, María I.,Díaz, José-Luis,Slee, Deborah H.
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experimental part
p. 7099 - 7110
(2009/11/30)
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- SUBSTITUTED PYRIMIDINES AS ADENOSINE RECEPTOR ANTAGONISTS
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Compounds of formula(I): wherein R1, R2 and R3 are as defined herein, including pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof.
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