- From a Designer Drug to the Discovery of Selective Cannabinoid Type 2 Receptor Agonists with Favorable Pharmacokinetic Profiles for the Treatment of Systemic Sclerosis
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Synthetic cannabinoids, as exemplified by SDB-001 (1), bind to both CB1 and CB2 receptors and exert cannabimimetic effects similar to (-)-trans-Δ9-tetrahydrocannabinol, the main psychoactive component present in the cannabis plant. As CB1 receptor ligands were found to have severe adverse psychiatric effects, increased attention was turned to exploiting the potential therapeutic value of the CB2 receptor. In our efforts to discover novel and selective CB2 receptor agonists, 1 was selected as a starting point for hit molecule identification and a class of 1H-pyrazole-3-carboxamide derivatives were thus designed, synthesized, and biologically evaluated. Systematic structure-activity relationship investigations resulted in the identification of the most promising compound 66 as a selective CB2 receptor agonist with favorable pharmacokinetic profiles. Especially, 66 treatment significantly attenuated dermal inflammation and fibrosis in a bleomycin-induced mouse model of systemic sclerosis, supporting that CB2 receptor agonists might serve as potential therapeutics for treating systemic sclerosis.
- Jiang, Bei-Er,Jiang, Xingwu,Zhang, Qiansen,Liang, Qiuwen,Qiu, Zi-Liang,Sun, Xiang-Bai,Yang, Jun-Jie,Chen, Si,Yi, Chunyang,Chai, Xiaolei,Liu, Mingyao,Yu, Li-Fang,Lu, Weiqiang,Zhang, Han-Kun
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p. 385 - 403
(2021/02/05)
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- The discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine cannabinoid type 2 receptor agonist
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The development of selective CB2 receptor agonists is a promising therapeutic approach for the treatment of inflammatory diseases, without CB1 receptor mediated psychoactive side effects. Preliminary structure-activity relationship studies on pyrazoylidene benzamide agonists revealed the -ylidene benzamide moiety was crucial for functional activity at the CB2 receptor. A small library of compounds with varying linkage moieties between the pyrazole and substituted phenyl group has culminated in the discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine agonist 19 (CB2R EC50 = 19 nM, CB1R EC50 > 10 μM). Docking studies have revealed key structural features of the linkage group that are important for potent functional activity.
- Moir, Michael,Lane, Samuel,Montgomery, Andrew P.,Hibbs, David,Connor, Mark,Kassiou, Michael
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- Nitrogen-containing five-membered heteroaromatic compound and preparation method and application thereof
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The invention discloses a nitrogen-containing five-membered heteroaromatic compound as shown in structural formulae (I) and (II), a medicinal derivative, a hydrate, a composition containing the nitrogen-containing five-membered heteroaromatic compound and a preparation method thereof. The invention also disclose an application of the compound as a drug and as a cannabinoid acceptor adjustor for preventing and treating ache, inflammation, immune diseases and central nervous system diseases and the like.
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Paragraph 0182; 0183
(2019/04/13)
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- The First Example of Azole-Fused Cyclic Anhydride Reacting in the Castagnoli-Cushman Way
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Pyrazole-fused cyclic anhydrides have been employed for the first time as the Castagnoli-Cushman reaction partners to produce hitherto unknown 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a ]pyrazine-7-carboxylates in remarkably convenient and speedy fashion. At
- Moreau, Ella,Dar'In, Dmitry,Krasavin, Mikhail
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p. 890 - 893
(2018/03/06)
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- Pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists
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A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S-configuration, providing exceptionally potent antagonists 13S and 16S with Ki(CAP) = 0.1 nM. Particularly significant, 13S exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for rTRPV1, blocking in vivo the hypothermic action of capsaicin, consistent with their in vitro mechanism. The docking study of compounds 13S and 16S in our hTRPV1 homology model indicated that the binding modes differed somewhat, with that of 13S more closely resembling that of GRT12360.
- Lee, Sunho,Kim, Changhoon,Ann, Jihyae,Thorat, Shivaji A.,Kim, Eunhye,Park, Jongmi,Choi, Sun,Blumberg, Peter M.,Frank-Foltyn, Robert,Bahrenberg, Gregor,Stockhausen, Hannelore,Christoph, Thomas,Lee, Jeewoo
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p. 4383 - 4388
(2017/09/12)
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- N-Substituted pyrazole-3-carboxamides as inhibitors of human 15-lipoxygenase
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High-throughput screening was used to find selective inhibitors of human 15-lipoxygenase-1 (15-LOX-1). One hit, a 1-benzoyl substituted pyrazole-3-carboxanilide (1a), was used as a starting point in a program to develop potent and selective 15-LOX-1 inhibitors.
- Pelcman, Benjamin,Sanin, Andrei,Nilsson, Peter,Schaal, Wesley,Olofsson, Kristofer,Krog-Jensen, Christian,Forsell, Pontus,Hallberg, Anders,Larhed, Mats,Boesen, Thomas,Kromann, Hasse,Claesson, Hans-Erik
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p. 3017 - 3023
(2015/06/22)
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- Synthesis of 3-aminomethyl-substituted pyrazoles and isoxazoles
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A series of new 3-(aminomethyl)pyrazoles and 3-(aminomethyl)isoxazoles was synthesized along a route involving the formation as key intermediates of esters of 5-substituted 1H-pyrazole-3-carboxylic and 1H-isoxazole-3-carboxylic acids. All compounds obtain
- Musatov,Starodubtseva,Rakishev,Turova,Vinogradov
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experimental part
p. 1199 - 1203
(2011/12/15)
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- NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE and INFLAMMATORY DISEASES
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The present invention relates to compounds that are inhibitors of PDElA, a phosphodiesterase that is involved in the modulation of the degradation of cartilage, joint degeneration and diseases involving such degradation and/or inflammation, and particular
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Page/Page column 43
(2009/07/17)
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- PYRAZOLEPYRIMIDINE COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE and INFLAMMATORY DISEASES
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The present invention relates to compounds that are inhibitors of PDElA, a phosphodiesterase that is involved in the modulation of the degradation of cartilage, joint degeneration and diseases involving such degradation and/or inflammation, and particular
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Page/Page column 43
(2009/07/17)
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- Novel compounds useful for the treatment of degenerative and inflammatory diseases
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The present invention relates to compounds that are inhibitors of PDE1A, a phosphodiesterase that is involved in the modulation of the degradation of cartilage, joint degeneration and diseases involving such degradation and/or inflammation.
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Page/Page column 24
(2008/12/07)
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- Agonist lead identification for the high affinity niacin receptor GPR109a
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A strategy for lead identification of new agonists of GPR109a, starting from known compounds shown to activate the receptor, is described. Early compound triage led to the formulation of a binding hypothesis and eventually to our focus on a series of pyrazole acid derivatives. Further elaboration of these compounds provided a series of 5,5-fused pyrazoles to be used as lead compounds for further optimization.
- Gharbaoui, Tawfik,Skinner, Philip J.,Shin, Young-Jun,Averbuj, Claudia,Jung, Jae-Kyu,Johnson, Benjamin R.,Duong, Tracy,Decaire, Marc,Uy, Jane,Cherrier, Martin C.,Webb, Peter J.,Tamura, Susan Y.,Zou, Ning,Rodriguez, Nathalie,Boatman, P. Douglas,Sage, Carleton R.,Lindstrom, Andrew,Xu, Jerry,Schrader, Thomas O.,Smith, Brian M.,Chen, Ruoping,Richman, Jeremy G.,Connolly, Daniel T.,Colletti, Steven L.,Tata, James R.,Semple, Graeme
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p. 4914 - 4919
(2008/02/12)
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- THERAPEUTIC AGENT FOR DIABETES
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The present invention provides an agent for the prophylaxis or treatment of diabetes, which is associated with a ferwer side effects such as body weight gain, adipocyte accumulation, cardiac hypertrophy and the like, and which contains a compound represented by the formula: wherein each symbol is as defined in the specification, or a salt thereof or a prodrug thereof.
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Page/Page column 143-144
(2008/06/13)
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- New modifications to the area of pyrazole-naphthyl urea based p38 MAP kinase inhibitors that bind to the adenine/ATP site
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Discovery of the pyrazole-naphthyl urea class of p38 MAP kinase inhibitors typified by the clinical candidate BIRB 796 has encouraged further exploration of this particular scaffold. Modification to the part of the inhibitor that occupies the adenine/ATP
- Moss, Neil,Breitfelder, Steffen,Betageri, Raj,Cirillo, Pier F.,Fadra, Tazmeen,Hickey, Eugene R.,Kirrane, Thomas,Kroe, Rachel R.,Madwed, Jeffrey,Nelson, Richard M.,Pargellis, Christopher A.,Qian, Kevin C.,Regan, John,Swinamer, Alan,Torcellini, Carol
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p. 4242 - 4247
(2008/02/09)
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- FUNGICIDAL HETEROCYCLIC COMPOUNDS
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A compound which can specifically or selectively expresses an antifungal activity with a broad spectrum, based on the functional mechanism of 1,6-β-glucan synthesis inhibition, is provided, and an antifungal agent which comprises such a compound, a salt thereof or a solvate thereof is provided. A compound represented by the following formula (I), a salt thereof or a solvate thereof.
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Page/Page column 96
(2010/11/24)
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- Microwave-assisted synthesis of pyrazoles by 1,3-dipolar cycloaddition of diazo compounds to acetylene derivatives
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Microwave-assisted preparation of a wide range of 5-ethoxycarbonylpyrazoles and 3-pyrazoles by 1,3-dipolar cycloaddition of diazo compound to acetylenes is described. All reactions were carried out using high throughput sequential technique.{A figure is p
- Zrinski, Irena,Juribasic, Marina,Eckert-Maksic, Mirjana
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p. 1961 - 1967
(2007/10/03)
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- HETEROYCLYLPHENYL-AND HETEROCYCLYLPYRIDYL-SUBSTITUTED AZOLECARBOXAMIDES AS HERBICIDES
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Compounds of Formula (I), and their N-oxides and agriculturally suitable salts, are disclosed which are useful for controlling undesired vegetation : wherein (J) is (J-1), (J-2), (J-3), (J-4), (J-5), (J-6), (J-7), (J-8), or (J-9) ; R5 is a phenyl ring or a 5- or 6-membered heteroaromatic ring which includes at least one heteroatom selected from N, O and S, each ring optionally substituted with one or more substituents selected from R15; or R5 is a 5- or 6-membered partially unsaturated heterocyclic ring which includes at least one heteroatom selected form N, O and S, the ring connected through a nitrogen atom or an sp2 carbon atom to the remainder of Formula (I) and optionally substituted by one or more substituents selected from R16; and R1a, R1b, R2a, R2b, R3, R4, R15, R16, T, U, W, Y and Z are as defined in the disclosure.
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Page/Page column 55
(2010/02/11)
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- AZOLECARBOXAMIDE HERBICIDES
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Compounds of Formula (I), and their N-oxides and agriculturally suitable salts, are disclosed which are useful for controlling undesired vegetation, wherein J is (J-1), (J-2,(J-3), (J-4), (J-5), (J-6), (J-7), (J-8) and R1a, R1b, R1c, R2a, R2b, R3, R4, R05, T, U, W, Y and Z are as defined in the disclosure. Also disclosed are compositions containing the compounds of Formula (I) and a method for controlling undesired vegetation which involves contacting the vegetation or its environment with an effective amount of a compound of Formula (I). Also disclosed are mixtures and compositions comprising a herbicidally effective amount of a compound of Formula (Iz) wherein J, R1a, R1b, R1c, R2a, R2b, R3, R4, R05, T, U, W, Y and Z are as defined in the disclosure; and an effective amount of another herbicide or herbicide safener. Also disclosed is a method for selectively controlling undesired vegetation in a crop that involves contacting the locus of a crop with an effective amount of a compound of Formula (Iz) and a effective amount of a safener.
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