- Discovery of [1,2,4]Triazolo[1,5- a]pyridine Derivatives as Potent and Orally Bioavailable RORγt Inverse Agonists
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The retinoic acid receptor-related orphan nuclear receptor γt (RORγt), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORγt with 1a, an analogue of the known piperazine RORγt inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analogue 3a was found to be a potent RORγt inverse agonist. Structure-activity relationship studies on 3a, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analogue, namely, 6-methyl-N-(7-methyl-8-(((2S,4S)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)butanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong RORγt inhibitory activity and a favorable pharmacokinetic profile. Moreover, the in vitro and in vivo evaluation of 5a in a human whole-blood assay and a mouse IL-18/23-induced cytokine expression model revealed its robust and dose-dependent inhibitory effect on IL-17A production.
- Nakajima, Ryota,Oono, Hiroyuki,Sugiyama, Sakae,Matsueda, Yohei,Ida, Tomohide,Kakuda, Shinji,Hirata, Jun,Baba, Atsushi,Makino, Akito,Matsuyama, Ryo,White, Ryan D.,Wurz, Ryan P.,Shin, Youngsook,Min, Xiaoshan,Guzman-Perez, Angel,Wang, Zhulun,Symons, Antony,Singh, Sanjay K.,Mothe, Srinivasa Reddy,Belyakov, Sergei,Chakrabarti, Anjan,Shuto, Satoshi
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supporting information
p. 528 - 534
(2020/03/13)
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- 6-AZAINDOLE COMPOUNDS
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Disclosed are compounds of Formula (I) N-oxides, or salts thereof, wherein A, G, R1, R5, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptor 7, or 8, or 9, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory and autoimmune diseases.
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Page/Page column 81
(2019/07/13)
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- PYRROLO[2,3-C]PYRIDINES AND RELATED ANALOGS AS LSD-1 INHIBITORS
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The present disclosure provides compounds represented by Formula I and II: and the pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, R3, X, W, Y, and Z are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I and II for use to treat a condition or disorder responsive to LSD1 inhibition such as cancer.
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Paragraph 0244; 0245; 0246
(2018/12/13)
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- Discovery of an HIV integrase inhibitor with an excellent resistance profile
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In the present article, we describe SAR studies within a series of N-hydroxy-dihydronaphthyridinone HIV integrase inhibitors that led to a candidate compound, PF-4776548, of high potency and with an excellent resistance profile. Uncertainties around the h
- Pryde, David C.,Webster, Rob,Butler, Scott L.,Murray, Edward J.,Whitby, Kevin,Pickford, Chris,Westby, Mike,Palmer, Michael J.,Bull, David J.,Vuong, Hannah,Blakemore, David C.,Stead, Darren,Ashcroft, Christopher,Gardner, Iain,Bru, Claire,Cheung, Wai-Yee,Roberts, Ieuan O.,Morton, Jennifer,Bissell, Richard A.
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p. 709 - 719
(2013/06/05)
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- NOVEL MICROBIOCIDES
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Compounds of the formula (I) in which the substituents are as defined in claim 1 are suitable for use as microbiocides.
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Page/Page column 89-90
(2008/12/08)
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