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Title: Pyrazolopyridines as phosphodiesterase inhibitors for respiratory disease
Author: Blakli, Haakon
ISNI:       0000 0001 3467 5506
Awarding Body: Heriot-Watt University
Current Institution: Heriot-Watt University
Date of Award: 2007
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Synthetic chemistry was explored to expand a series of 6-(pyrazolo[1,5-a]pyridin-3-yl)-2Hpyridazin- 3-one phosphodiesterase (PDE) inhibitors with therapeutic potential for treatment of asthma. The synthetic route to these compounds featured a 1,3-dipolar cycloaddition reaction between a pyridine N-imine and 4-oxoalk-5-ynoate ester to generate a pyrazolopyridine substituted at C-3 with a y-keto ester side chain. Hydrazine condensation of the latter established the 4,5-dihydro-2H-pyridazin-3-one ring. Treatment with bromine in acetic acid allowed conversion of the dihydropyridazinone into the corresponding pyridazinone. N(2)-alkylation was accomplished by treatment of the (dihydro)pyridazinones with alkyl bromides and base in N,N-dimethylformamide. The introduction of a 7-methoxy group on the pyrazolopyridine unit in combination with an N(2)-benzyl substituent on the (dihydro)pyridazinone strongly improved potency for inhibition of PDE type 4 and conferred selectivity over PDEs 3 and 5. This indicated that the compound series is structurally related to an established group of PDE4-selective inhibitors containing a catechol ether core structure. Inspection of known catechol ether PDE4 inhibitors suggested that reseating the pyridazinone ring from the pyrazolopyridine C-3 centre to C-4 may enhance the PDE4-inhibitory potency of the compound series. New synthetic routes for the preparation of 6-(pyrazolo[1,5-a]pyridin-4-yl)-2H-pyridazin3- ones were therefore explored. A practicable route to these compounds commenced with 2,3-dibromo-6-methoxypyridine. Sonogashira coupling with 3-methyl-l-butyne occurred selectively at the pyridine 2-position to afford 3-bromo-6-methoxy-2-(3-methylbut-lynyl) pyridine. N-amination using O-mesitylenesulfonyl-hydroxylamine followed by treatment of the intermediate N-aminopyridinium salt with base afforded 4-bromo-2isopropyl- 7-methoxypyrazolo[1,5-a]pyridine. The latter was lithiated and treated with trimethyl borate to generate a pyrazolopyridine-4-boronic acid. Suzuki coupling of the latter with 3,6-dichloropyridazine or 6-chloropyridazin-3(2H)-one derivatives completed the core skeleton. 2-Benzyl-6-(2-isopropyl-7-methoxypyrazolo[1,5-a]pyridin-4yl) pyridazin-3(2H)-one, representative of the target compounds, exhibited potent PDE4 inhibition (ICso 55 nM) representing 3 orders of magnitude activity enhancement over the 6-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-one parent structure with which the project commenced
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available