2. Academic Validation
  3. 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

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

  • J Med Chem. 2008 Nov 27;51(22):7099-110. doi: 10.1021/jm800851u.
Xiaohu Zhang 1,  John E Tellew,  Zhiyong Luo,  Manisha Moorjani,  Emily Lin,  Marion C Lanier,  Yongsheng Chen,  John P Williams,  John Saunders,  Sandra M Lechner,  Stacy Markison,  Tanya Joswig,  Robert Petroski,  Jaime Piercey,  William Kargo,  Siobhan Malany,  Mark Santos,  Raymond S Gross,  Jenny Wen,  Kayvon Jalali,  Zhihong O'Brien,  Carol E Stotz,  María I Crespo,  José-Luis Díaz,  Debora H Slee
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Neurocrine Biosciences, 12780 El Camino Real, San Diego, California 92130, USA.
PMID: 18947224 DOI: 10.1021/jm800851u
Abstract

4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA2A 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.

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