- INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION
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Compounds and pharmaceutically acceptable salts thereof, and compositions and methods for treating human immunodeficiency virus (HIV) infection are set forth.
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Page/Page column 64
(2020/06/01)
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- 2-AMINO-N-PHENYL-NICOTINAMIDES AS NAV1.8 INHIBITORS
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Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are inhibitors of Nav1.8 channel activity and may be useful in the treatment, prevention, management, amelioration, control and suppression of diseases mediated by Nav1.8 channel activity. The compounds of the present invention may be useful in the treatment, prevention or management of pain disorders, cough disorders, acute itch disorders, and chronic itch disorders.
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Page/Page column 85
(2020/05/28)
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- Halogenated allyl amine type SSAO/VAP-1 inhibitor and application thereof
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The invention belongs to the technical field of medicine, and particularly relates to a halogenated allyl amine type compound shown as a formula I, medically acceptable salt, ester or stereo isomers thereof, wherein R1, R2, R3, R4, R5, R6, L1, Cy1, R7 and p are defined in description. The invention also relates to a medicine preparation containing the compounds, a medicine composition containing the compounds, and application of the compounds to prevention and/or treatment on diseases relevant to SSAO/VAP 1 protein or diseases caused by SSAO/VAP 1 protein mediating. The formula I is shown in the description.
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Paragraph 0315; 0322-0324
(2019/06/08)
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- Structure-Guided Optimization of HIV Integrase Strand Transfer Inhibitors
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Integrase mutations can reduce the effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogues of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogues we have previously described.
- Zhao, Xue Zhi,Smith, Steven J.,Maskell, Daniel P.,Métifiot, Mathieu,Pye, Valerie E.,Fesen, Katherine,Marchand, Christophe,Pommier, Yves,Cherepanov, Peter,Hughes, Stephen H.,Burke, Terrence R.
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p. 7315 - 7332
(2017/09/22)
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- ARYLCARBOXAMIDES AND USES THEREOF
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The present disclosure is directed to compounds of formula (I): or a pharmaceutically acceptable salt, solvate or solvate of the salt thereof. Compounds of formula (I) are inhibitors of NOX4 and are useful in the treatment of fibrotic diseases such as scleroderma; lung disease, such as pulmonary fibrosis including idiopathic pulmonary fibrosis (IPF); heart disease, such as heart failure due to ischaemic heart disease, valvular heart disease and hypertensive heart disease, diabetic cardiomyopathy and hypertension; liver disease, such as cirrhosis of the liver; and kidney disease, such as progressive kidney disease glomerulonephritis and diabetic nephropathy; and eye disease such as diabetic retinopathy; skin or subcutaneous scarring, such as keloids, adhesions, hypertrophic scarring or cosmetic scarring; or as an adjuvant or anti-fibrotic in pancreatic cancer to increase chemotherapeutic drug penetration by reducing the density of the connective tissue stroma.
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Paragraph 0279
(2017/12/13)
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- From 2,6-dichloronicotinic acid to thiopeptide cores
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The scope of 2,6-dichloronicotinic acid as a precursor of thiopeptide polyheterocylic cores has been extensively studied in a cross-coupling-based approach. Differentiation of the two chlorinated positions under SNAr conditions and versatility of the carboxylic acid are key for the preparation of 2,3,6-trisubstituted pyridines with complete regiocontrol. With the present strategy, nine different azole-substituted pyridines were synthesized. Studies towards the selective deprotection of their functionalities resulted in a set of fully orthogonal protecting groups that permits the elongation of all three pyridine substituents. Copyright
- Just-Baringo, Xavier,Albericio, Fernando,Alvarez, Mercedes
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p. 6404 - 6419
(2013/10/21)
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- AZAQUINOLONE BASED COMPOUNDS EXHIBITING PROLYL HYDROXYLASE INHIBITORY ACTIVITY, COMPOSITIONS, AND USES THEREOF
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Compounds of Formula (I) are useful as inhibitors of HIF prolyl hydroxylases where the definitions of the variables are provided herein.
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- Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity
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A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D2 and serotonin 5-HT3 receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT3 receptor along with moderate to high binding affinity for the dopamine D2 receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D2 receptor while keeping a potent serotonin 5-HT3 receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D2 and serotonin 5-HT3 receptors was much more potent than that of metoclopramide (dopamine D2 receptor; 23.3 nM vs 444 nM, serotonin 5-HT3 receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)- 53 exhibiting a strong affinity for both the dopamine D2 and serotonin 5-HT3 receptors, while the corresponding (S)-53 had a potent serotonin 5-HT3 receptor binding affinity and a moderate dopamine D2 receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D2 and serotonin 5-HT3 receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D2 and serotonin 5-HT3 receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID50 values of 27.1, μg/kg, po and 136 μg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.
- Hirokawa, Yoshimi,Fujiwara, Iwao,Suzuki, Kenji,Harada, Hiroshi,Yoshikawa, Takashi,Yoshida, Naoyuki,Kato, Shiro
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p. 702 - 715
(2007/10/03)
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- An efficient synthesis of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid
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An efficient synthesis of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid (1), a carboxylic acid moiety of a potent dopamine D2 and D3 and serotonin-3 (5-HT3) receptors antagonist, (R)-5-bromo-N-(1-ethyl-4-methyl
- Hirokawa,Horikawa,Kato
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p. 1847 - 1853
(2007/10/03)
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