- Aminothienopyridazine inhibitors of tau aggregation: Evaluation of structure-activity relationship leads to selection of candidates with desirable in vivo properties
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Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4- dihydrothieno[3,4-d]pyridazine-1-carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50 mg/kg/day.
- Ballatore, Carlo,Crowe, Alex,Piscitelli, Francesco,James, Michael,Lou, Kevin,Rossidivito, Gabrielle,Yao, Yuemang,Trojanowski, John Q.,Lee, Virginia M.-Y.,Brunden, Kurt R.,Smith III, Amos B.
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experimental part
p. 4451 - 4461
(2012/08/28)
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- 2-Aminothienopyridazines as novel adenosine A1 receptor allosteric modulators and antagonists
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A pharmacophore-based screen identified 32 compounds including ethyl 5-amino-3-(4-tert-butylphenyl)-4-oxo-3,4-dihydrothieno[3,4-d] pyridazine-1-carboxylate (8) as a new allosteric modulator of the adenosine A1 receptor (A1AR). On the basis of this lead, various derivatives were prepared and evaluated for activity at the human A 1AR. A number of the test compounds allosterically stabilized agonist-receptor-G protein ternary complexes in dissociation kinetic assays, but were found to be more potent as antagonists in subsequent functional assays of ERK1/2 phosphorylation. Additional experiments on the most potent antagonist, 13b, investigating A1AR-mediated [35S]GTPγS binding and [3H]CCPA equilibrium binding confirmed its antagonistic mode of action and also identified inverse agonism. This study has thus identified a new class of A1AR antagonists that can also recognize the receptor's allosteric site with lower potency.
- Ferguson, Gemma N.,Valant, Celine,Horne, James,Figler, Heidi,Flynn, Bernard L.,Linden, Joel,Chalmers, David K.,Sexton, Patrick M.,Christopoulos, Arthur,Scammells, Peter J.
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experimental part
p. 6165 - 6172
(2009/10/09)
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- Studies on Alkyl Heterocyclic Aromatic Compounds: New Routes for the Synthesis of Polyazanaphthalenes
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Several new polyfunctionally substituted polyazanaphthalene derivatives could be synthesized via condensing readily obtainable polyfunctional nitriles with substituted akyl heteroaromatic derivatives and reacting the latter derivatives with electrophilic
- Elnagdi, Mohamed Hilmy,Aal, Fatma Abdel Maksoud Abdel,Hafez, Ebtisam Abdel Aziz,Yassin, Youssef Mahfouz
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p. 683 - 689
(2007/10/02)
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- STUDIES ON ALKYLHETEROAROMATIC COMPOUNDS. THE REACTIVITY OF ALKYL POLYFUNCTIONALLY SUBSTITUTED AZINES TOWARDS ELECTROPHILIC REAGENTS
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Several new alkylpyridine, pyridazine and pyrimidine derivatives are synthesized from acyclic intermediates.The reactivity of these alkylazines towards aromatic aldehydes and arylidenemalononitrile is reported.New synthesis for substituted phthalazines ci
- Elnagdi, Mohamed Hilmy,Abdelrazek, Fathy Mohamed,Ibrahim, Nadia Sobhy,Erian, Ayman Wahba
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p. 3597 - 3604
(2007/10/02)
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