- Synthesis and evaluation of nevirapine analogs to study the metabolic activation of nevirapine
-
Nevirapine (NVP) is widely used as a non-nucleoside reverse transcriptase inhibitor of HIV-1, however, it is associated with severe skin and liver injury. The mechanisms of these adverse reactions are not yet clear, but the metabolic activation of NVP is thought to be related to the injury process. Until now, several metabolic activation pathways of NVP have been reported. In this study, in order to identify the reactive metabolite of NVP mainly responsible for CYP inhibition and liver injury, we synthesized five NVP analogs designed to avoid the proposed bioactivation pathway and evaluated their metabolic stabilities, CYP3A4 time-dependent inhibitory activities, and cytotoxicity. As a result, only a pyrimidine analog of NVP, which could avoid the formation of a reactive epoxide intermediate, did not inhibit CYP3A4. Outside of this compound, the other synthesized compounds, which could avoid the generation of a reactive quinone-methide intermediate, inhibited CYP3A4 equal to or stronger than NVP. The pyrimidine analog of NVP did not induce cytotoxicity in HepG2 and transchromosomic HepG2 cells, expressing major four CYP enzymes and CYP oxidoreductase. These results indicated that the epoxide intermediate of NVP might play an important role in NVP-induced liver injury.
- Kazuki, Yasuhiro,Mashino, Tadahiko,Nakamura, Shigeo,Ohe, Tomoyuki,Takahashi, Kyoko,Tateishi, Yasuhiro,Yasuda, Daisuke
-
-
- Design, synthesis, and bioactivities of novel pyridazinone derivatives containing 2-phenylthiazole or oxazole skeletons
-
A series of novel pyridazinone derivatives were designed and synthesized by replacing 4-(tert-butyl)phenyl moiety of pyridaben with 2-phenylthiazole or oxazole fragments via activity substructure connecting approach. The structures of all target compounds were characterized through NMR, MS, and elemental analysis. Bioassay results exhibit that most compounds showed potent bioactivities against Aphis fabae, Tetranychus urticae, Erysiphe graminis, and/or Puccinia polysora. Among the newly synthesized compounds, 2-(tert-butyl)-4-chloro-5-(((2-phenylthiazol-4-yl)methyl)thio)pyridazin-3(2H)-one (12b) displays remarkable insecticidal activity against A fabae. Its LC50 value (2.73 mg/L) is better than that of pyridaben (5.46 mg/L), although inferior to that of imidacloprid (0.51 mg/L). In addition to its extraordinary insecticidal activity, compound 12b also exerts 96.9% fungicidal activities against P polysora at 500 mg/L in vivo, significantly superior to that of pyridaben (50.0%), while slightly lower than that of tebuconazole (100%). This article discusses the synthesis, bioassay results, and structure-activity relationship of this series of novel pyridazinone derivatives.
- Dang, Mingming,Liu, Minhua,Huang, Lu,Ou, Xiaoming,Long, Chuyun,Liu, Xingping,Ren, Yeguo,Zhang, Ping,Huang, Mingzhi,Liu, Aiping
-
p. 4088 - 4098
(2020/10/02)
-
- NOVEL NITROGEN-CONTAINING AROMATIC HETEROCYCLIC COMPOUND
-
A compound represented by general formula [1] wherein X represents N or the like, Y represents CH or the like; RA represents a cycloalkyl group which may be substituted or the like, R1 represents an alkyl group or the like, R2 represents an alkyl group which may be substituted or the like, R3 represents a hydrogen atom or an alkyl group, or a pharmaceutically acceptable salt thereof has an inhibitory activity on aldosterone synthetase, and is useful as a prophylactic and/or therapeutic agent for various diseases or symptoms associated with aldosterone.
- -
-
Paragraph 0135
(2018/10/15)
-
- One-Pot Highly Regioselective Synthesis of Indole-Fused Pyridazino[4,5- b ][1,4]benzoxazepin-4(3 H)-ones by a Smiles Rearrangement
-
A simple and convenient synthesis of indole-fused pyridazino[4,5- b ][1,4]benzoxazepin-4(3 H)-ones is described. A range of 2-(1 H -indol-2-yl)phenols and 4,5-dichloropyridazin-3-ones are compatible with this reaction. A Smiles rearrangement is proposed as a key step in the highly regioselective construction of the products. The easy availability of the starting materials makes this an appealing method in organic synthesis.
- Jiang, Xiaolei,Hu, Fangdong
-
supporting information
p. 1207 - 1210
(2018/03/23)
-
- Discovery of a new series of potent prostacyclin receptor agonists with in vivo activity in rat
-
The design and synthesis of two closely related series of prostacyclin receptor agonist compounds that showed excellent human IP receptor potency and efficacy is described. Compounds from this series showed in vivo activity after SC dosing in the monocrotaline model of PAH in rat.
- Tran, Thuy-Anh,Shin, Young-Jun,Kramer, Bryan,Choi, Juyi,Zou, Ning,Vallar, Pureza,Martens, Peter,Douglas Boatman,Adams, John W.,Ramirez, Juan,Shi, Yunqing,Morgan, Michael,Unett, David J.,Chang, Steve,Shu, Hsin-Hui,Tung, Shiu-Feng,Semple, Graeme
-
supporting information
p. 1030 - 1035
(2015/02/19)
-
- IMIDAZO[1,2-a]PYRIDINES AND IMIDAZO[1,2-b]PYRIDAZINES AS MARK INHIBITORS
-
The invention encompasses imidazo[1,2-a]pyridine and imidazo[1,2-b]pyridazine derivatives which selectively inhibit microtubule affinity regulating kinase (MARK) and are therefore useful for the treatment or prevention of Alzheimer's disease. Pharmaceutical compositions and methods of use are also included.
- -
-
Page/Page column 25
(2010/08/08)
-
- CASPASE INHIBITORS BASED ON PYRIDAZINONE SCAFFOLD
-
The present invention relates to a pyridazinone derivative which can be used as a caspase inhibitor, process for the preparation thereof, and pharmaceutical composition for inhibiting caspase comprising the same.
- -
-
Page/Page column 30-31
(2008/06/13)
-
- PYRIDAZINONES AND FURAN-CONTAINING COMPOUNDS
-
The present invention is directed to pyridazinone compounds of formula (I) and furan compounds of formula (II), pharmaceutical compositions of compounds of formula (I) and (II), kits containing these compounds, methods of syntheses, and a method of treatment of a proliferative disease in a subject by administration of a therapeutically effective amount of a compound of formulae (I) or (II). Both classes of compounds were identified through screening of a collection of small molecule libraries.
- -
-
Page/Page column 94; 96
(2008/12/07)
-
- Azabicyclic heterocycles as cannabinoid receptor modulators
-
The present application describes compounds according to Formula I, pharmaceutical compositions comprising at least one compound according to Formula I and optionally one or more additional therapeutic agents and methods of treatment using the compounds according to Formula I both alone and in combination with one or more additional therapeutic agents. The compounds have the general Formula I and Formula II: including all prodrugs, pharmaceutically acceptable salts and stereoisomers, R1, R2, R3 and R4 are described herein.
- -
-
Page/Page column 12
(2008/06/13)
-
- Azabicyclic heterocycles as cannabinoid receptor modulators
-
The present application describes compounds according to Formula I, pharmaceutical compositions comprising at least one compound according to Formula I and optionally one or more additional therapeutic agents and methods of treatment using the compounds according to Formula I both alone and in combination with one or more additional therapeutic agents. The compounds have the general Formula I: including all prodrugs, pharmaceutically acceptable salts and stereoisomers, R1, R2, R3, R6, R7, m and n are described herein.
- -
-
Page/Page column 79
(2008/06/13)
-
- Macrocyclic hepatitis C serine protease inhibitors
-
The present invention relates to compounds of Formula I, II or Ill, or a pharmaceutically acceptable salt, ester, or prodrug, thereof: wherein W is a substituted or unsubstituted heterocyclic ring system. The compounds inhibit serine protease activity, particularly the activity of hepatitis c virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis c virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.
- -
-
Page/Page column 165-166
(2008/06/13)
-
- Synthesis of new pyridazino[4,5-c]isoquinolinones by Suzuki cross-coupling reaction
-
Suzuki cross-coupling reaction of 2-alkyl(methyl and benzyl)-5-chloro-4-methoxy- and 2-alkyl(methyl and benzyl)-4-chloro-5-methoxypyridazin-3(2H)-ones with 2-formylphenylboronic acid afforded the corresponding biaryl products which were cyclized with ammonia to yield hitherto undescribed pyridazino[4,5-c]isoquinolinones. Removal of the N-benzyl protective group in position 2 yielded the unsubstituted tricyclic pyridazinones.
- Riedl, Zsuzsanna,Maes, Bert U.W,Monsieurs, Katrien,Lemière, Guy L.F,Mátyus, Péter,Hajós, Gy?rgy
-
p. 5645 - 5650
(2007/10/03)
-
- Synthesis of 4-aryl-5-hydroxy- and 5-aryl-4-hydroxypyridazin-3(2H)-ones and their use in the preparation of 4,5-diarylpyridazin-3(2H)-ones and hitherto unknown isochromeno[3,4-d]pyridazinediones
-
Easily accessible 2-substituted 4-aryl-5-methoxy- and 2-substituted 5-aryl-4-methoxypyridazin-3(2H)-ones were transformed into the corresponding aryl-hydroxypyridazin-3(2H)-ones by alkaline hydrolysis. The use of these compounds in the synthesis of 2-substituted 4,5-diarylpyridazin-3(2H)-ones with two differently substituted aryl groups was investigated. Two aryl-hydroxypyridazin-3(2H)-ones, 2-(2-benzyl-5-hydroxy-3-oxo-2,3-dihydropyridazin-4-yl)benzaldehyde and 2-(1-benzyl-5-hydroxy-6-oxo-1,6-dihydropyridazin-4-yl)benzaldehyde, were transformed into 2-benzyl-1H-isochromeno[3,4-d]pyridazine-1,6(2H)-dione and 3-benzyl-3H-isochromeno[3,4-d]pyridazine-4,6-dione, respectively, via oxidation of the formyl group with KMnO4 followed by lactonization.
- Maes, Bert U.W,Monsieurs, Katrien,Loones, Kristof T.J,Lemière, Guy L.F,Dommisse, Roger,Mátyus, Péter,Riedl, Zsuzsanna,Hajós, Gy?rgy
-
p. 9713 - 9721
(2007/10/03)
-
- Synthesis of Novel Pyridazino[4,5-b][1,4]oxazine-3,5-diones
-
Novel pyridazino[4,5-b][1,4]oxazine-3,5-diones were synthesized from N-[2-(3,4-dimethoxyphenyl)-ethyl]-2-chloroacetamide (or 2-chloropropanamide) and 1-alkyl-5-halo-4-hydroxypyridazin-6-ones in good yield.
- Cho, Su-Dong,Kweon, Deok-Heon,Kang, Young-Jin,Chung, Hyun-A.,Yoon, Yong-Jin
-
p. 601 - 605
(2007/10/03)
-
- 3(2H)Pyridazinone, process for its preparation and anti-allergic agent containing it
-
A 3(2H)pyridazinone of the formula: STR1 wherein R1 is hydrogen, methyl, C3 -C6 alkenyl, C5 or C6 cycloalkyl, benzyl, phenyl, --(CH2)m CO2 R3 (wherein R3 is hydrogen or C1 -C5 alkyl, and m is an integer of from 1 to 4), --(CH2)n A (wherein A is --OH or --N(R4)2 wherein R4 is C1 -C3 alkyl, and n is an integer of from 2 to 6) or --CH2 CF3 ; R2 is chlorine or bromine; each of Y1 and Y2 which may be the same or different, is hydrogen, C1 -C5 alkyl, C2 -C8 alkenyl, halogen, --OR5 (wherein R5 is hydrogen, C1 -C8 alkyl or STR2 wherein q is an integer of from 1 to 4), --CO2 R6 (wherein R6 is hydrogen or C1 -C5 alkyl), --N(R7)2 (wherein R7 is C1 -C4 alkyl) or --SR8 (wherein R8 is C1 -C4 alkyl); and Y3 is C1 -C5 alkyl, C2 -C8 alkenyl, halogen, --OR5 (wherein R5 is as defined above), --CO2 R6 (wherein R6 is as defined above), --N(R7)2 (wherein R7 is as defined above) or --SR8 (wherein R8 is as defined above), or a pharmaceutically acceptable salt thereof.
- -
-
-