| 1. |
- Besidski, Yevgeni, et al.
(författare)
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Preparation of aminotriazole compounds as gamma secretase modulators useful for treatment of Aβ-related diseases.
- 2014
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Patent (populärvet., debatt m.m.)abstract
- The invention relates to aminotriazole compds. of formula I and pharmaceutically acceptable salts and pharmaceutical compns. thereof, as well as processes for making these compds. for use in the treatment and/or prevention of Aβ-related diseases. I [wherein A is (un)substituted 5- or 6-membered heteroaryl ring comprising at least one N; R1 is H, C1-3-alkyl, cyano, etc.; R2 is (un)substituted C1-6-alkyl, C3-7-cycloalkyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl, etc.; R3 and R4 are each independently selected from H, C1-6-alkyl, (un)substituted C3-7-cycloalkyl, etc.] or pharmaceutically acceptable salts thereof are claimed and exemplified. Example compd. II was prepd. from the reaction of 3-bromo-N-(cyclopropylmethyl)-1-methyl-1H-1,2,4-triazol-5-amine with 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline dihydrochloride under Buchwald-Hartwig conditions in 26% yield. Nine compds. of I were evaluated for inhibition of Aβ formation utilizing electrochemiluminescence anal. and HEK cells expressing amyloid precursor protein (data given). [on SciFinder(R)]
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| 2. |
- Besidski, Yevgeni, et al.
(författare)
-
Preparation of azetidinotriazole compounds as gamma secretase modulators useful for treatment of Aβ-related diseases.
- 2014
-
Patent (populärvet., debatt m.m.)abstract
- The invention relates to azetidinotriazole compds. of formula I and pharmaceutically acceptable salts and pharmaceutical compns. thereof, as well as processes for making these compds. for use in the treatment and/or prevention of Aβ-related diseases. I [wherein A is (un)substituted 5- or 6-membered heteroaryl ring comprising at least one N; R1 is H, C1-3-alkyl, cyano, etc.; R2 is (un)substituted C1-6-alkyl, C3-7-cycloalkyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl, etc.; R3, R5, and R7 are each independently selected from H, (un)substituted C1-3-alkyl, C3-7-cycloalkyl, etc.; R4, R6, R8 are each independently selected from H, F, C1-3-alkyl, etc.; or R3 and R4, or R5 and R6, or R7 and R8, together with the carbon to which they are attached, form (un)substituted 3- to 7-membered satd. ring optionally contg. an O or N] or pharmaceutically acceptable salts thereof are claimed and exemplified. Example compd. II was prepd. from the reaction of III with 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline under Buchwald-Hartwig conditions in 26% yield. Nine compds. of I were evaluated for activity on Aβ formation utilizing electrochemiluminescence anal. and HEK cells expressing amyloid precursor protein (data given). [on SciFinder(R)]
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| 3. |
- Besidski, Yevgeni, et al.
(författare)
-
Preparation of pyrimidinylamine compounds as gamma secretase modulators useful for treatment of Aβ-related diseases.
- 2014
-
Patent (populärvet., debatt m.m.)abstract
- The invention relates to pyrimidinylamine compds. of formula I and pharmaceutically acceptable salts and pharmaceutical compns. thereof, as well as processes for making these compds. for use in the treatment and/or prevention of Aβ-related diseases. I [wherein A is (un)substituted 5- or 6-membered heteroaryl ring comprising at least one N; R1 is H, C1-3-alkyl, cyano, etc.; R2 and R3 are each independently selected from C1-3-alkyl and fluoro-C1-3-alkyl; or R2 and R3 together with the carbon to which they are attached form a 3- to 6-membered satd. carbocyclic ring, optionally substituted with one or more fluoro substituents; R4 is C1-3-alkyl, fluoro-C1-3-alkyl, or C3-6-cycloalkyl-C1-3-alkyl; R5 is H, C1-3-alkyl, fluoro, etc.; R6 is, for example, CH3NH-, CNCH2-, or MeO-] or pharmaceutically acceptable salts thereof are claimed and exemplified. Example compd. II was prepd. from the reaction of III with 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline under Buchwald-Hartwig conditions in 77% yield. Fifty-two compds. of I were evaluated for activity on Aβ formation utilizing electrochemiluminescence anal. and HEK cells expressing amyloid precursor protein (data given). [on SciFinder(R)]
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| 4. |
- Bylund, Johan, et al.
(författare)
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Novel bioactivation mechanism of reactive metabolite formation from phenyl methyl-isoxazoles
- 2012
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Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 40:11, s. 2185-2191
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Tidskriftsartikel (refereegranskat)abstract
- Recently, we described a series of phenyl methyl-isoxazole derivatives as novel, potent, and selective inhibitors of the voltage-gated sodium channel type 1.7 (Bioorg Med Chem Lett 21:3871-3876, 2011). The lead compound, 2-chloro-6-fluorobenzyl [3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]carbamate, showed unprecedented GSH and cysteine reactivity associated with NADPH-dependent metabolism in trapping studies using human liver microsomes. Additional trapping experiments with close analogs and mass spectra and NMR analyses suggested that the conjugates were attached directly to the 5′-methyl on the isoxazole moiety. We propose a mechanism of bioactivation via an initial oxidation of the 5′-methyl generating a stabilized enimine intermediate and a subsequent GSH attack on the 5′-methylene. Efforts to ameliorate reactive metabolite generation were undertaken to minimize the potential risk of toxicity. Formation of reactive metabolites could be significantly reduced or prevented by removing the 5′-methyl, by N-methylation of the carbamate; by replacing the nitrogen with a carbon or removing the nitrogen to obtain a carboxylate; or by inserting an isomeric 5′-methyl isoxazole. The effectiveness of these various chemical modifications in reducing GSH adduct formation is in line with the proposed mechanism. In conclusion, we have identified a novel mechanism of bioactivation of phenyl 5-methyl-isoxazol-4-yl-amines. The reactivity was attenuated by several modifications aimed to prevent the emergence of an enimine intermediate. Whether 5′-methyl isoxazoles should be considered a structural alert for potential formation of reactive metabolites is dependent on their context, i.e., 4′-nitrogen.
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| 5. |
- Macsari, Istvan, et al.
(författare)
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Phenyl isoxazole voltage-gated sodium channel blockers : structure and activity relationship
- 2011
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 21:13, s. 3871-3876
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Tidskriftsartikel (refereegranskat)abstract
- Blocking of certain sodium channels is considered to be an attractive mechanism to treat chronic pain conditions. Phenyl isoxazole carbamate 1 was identified as a potent and selective Na(V)1.7 blocker. Structural analogues of 1, both carbamates, ureas and amides, were proven to be useful in establishing the structure-activity relationship and improving ADME related properties. Amide 24 showed a good overall in vitro profile, that translated well to rat in vivo PK.
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| 6. |
- Yngve, Ulrika, et al.
(författare)
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Triazolopyrimidinones as gamma-secretase modulators : structure-activity relationship, modulator profile, and in vivo profiling
- 2013
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 4:2, s. 422-431
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Tidskriftsartikel (refereegranskat)abstract
- The structure-activity relationship for a series of potent g-secretase modulators based on the 6,7-dihydro4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one scaffold is described. Furthermore, we report details regarding the modulator profile on A beta processing, as well as in vivo efficacy, for the optimized compounds.
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