Kieran Durkin

Discovery of FR166124, a novel water-soluble pyrazolo-[1,5-a]pyridine adenosine A1 receptor antagonist

Novel 3-(2-cycloalkyl and cycloalkenyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazo lo [1,5-a]-pyridines were synthesized and evaluated for their adenosine A1 receptor binding activities. In this series, FR166124 (3) was found to be the most potent and selective adenosine A1 receptor antagonist, and the double bond of the cyclohexenyl acetic acid group was essential for selectivity of A1 receptor binding. Furthermore, the solubility in water of the sodium salt of FR 166124 was high.

3-Amino-pyrazolo[3,4-d]pyrimidines as p38α kinase inhibitors: Design and development to a highly selective lead

Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.

Novel adenosine A1 receptor antagonists. Synthesis and structure-activity relationships of a novel series of 3-(2-cyclohexenyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5 -a]pyridines.

A novel series of 3-(2-cyclohexenyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazol o[1,5-a]pyridines was synthesized and evaluated for in vitro adenosine A1 and A2A receptor binding activities. Most of the cyclohexenyl derivatives (7a-e, 8a-s) were found to be potent adenosine A1 receptor antagonists. In a series of analogues of FR166124 (3a), alcohol 7c, nitrile 7e and amide derivatives (7d, 8c, 8r) were found to be more potent A1 antagonists with higher A2A/A1 selectivity than FR166124. Amongst them, 8r showed considerable water solubility (33.3 mg/mL), but lower than that of the sodium salt of FR166124 (> 200 mg/mL). Additionally, FR166124 had strong diuretic activity by both p.o. and iv administration in rats (minimum effective dose=0.1 and 0.032 mg/kg, respectively).

SYNTHESIS OF THE WATER-SOLUBLE ADENOSINE A1 RECEPTOR ANTAGONIST FR166124 THROUGH A NOVEL SEQUENTIAL HORNER-EMMONS/ISOMERIZATION REACTION

Abstract An efficient synthesis of FR166124 ( 1 ) was achieved through a novel sequential Horner-Emmons -isomerization reaction of cyclohexanone ( 2 ) with tert -butyl diethylphosphonoacetate ( 3 ) as the key process. Extensive studies of the key reaction indicated that temperature, base and conformation of the Horner-Emmons products were important factors in the isomerization reaction, leading to a proposed mechanism for this unusual Horner-Emmons reaction.