- Structure-Activity Relationship Studies Reveal New Astemizole Analogues Active against Plasmodium falciparum in Vitro
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In the context of drug repositioning and expanding the existing structure-activity relationship around astemizole (AST), a new series of analogues were designed, synthesized, and evaluated for their antiplasmodium activity. Among 46 analogues tested, compounds 21, 30, and 33 displayed high activities against asexual blood stage parasites (PfNF54 IC50 = 0.025-0.043 μM), whereas amide compound 46 additionally showed activity against late-stage gametocytes (stage IV/V; PfLG IC50 = 0.6 ± 0.1 μM) and 860-fold higher selectivity over hERG (46, SI = 43) compared to AST. Several analogues displaying high solubility (Sol > 100 μM) and low cytoxicity in the Chinese hamster ovary (SI > 148) cell line have also been identified.
- Birkholtz, Lyn-Marie,Chibale, Kelly,Coertzen, Dina,Ferger, Richard,Kumar, Malkeet,Mambwe, Dickson,Njoroge, Mathew,Reader, Janette,Taylor, Dale,Van Der Watt, Mari?tte
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supporting information
p. 1333 - 1341
(2021/08/24)
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- 2-(BICYCLO-HETEROARYL)-ISONICOTINIC DERIVATIVES AS HISTONE DEMETHYLASE INHIBITORS
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The invention relates to compounds of Formula (I) as described herein, useful as histone demethylase inhibitors. The invention also relates to pharmaceutical compositions comprising these compounds and to their use in therapy, including e.g., in the treatment of cancer.
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Page/Page column 95
(2018/09/12)
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- Discovery of tertiary amine and indole derivatives as potent RORγt inverse agonists
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A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (RORγt) inverse agonists was discovered through agonist/inverse agonist conversion. The level of RORγt inhibition can be enhanced by modulating the conformational disruption of H12 in RORγt LBD. Linker exploration and rational design led to the discovery of more potent indole-based RORγt inverse agonists.
- Yang, Ting,Liu, Qian,Cheng, Yaobang,Cai, Wei,Ma, Yingli,Yang, Liuqing,Wu, Qianqian,Orband-Miller, Lisa A.,Zhou, Ling,Xiang, Zhijun,Huxdorf, Melanie,Zhang, Wei,Zhang, Jing,Xiang, Jia-Ning,Leung, Stewart,Qiu, Yang,Zhong, Zhong,Elliott, John D.,Lin, Xichen,Wang, Yonghui
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supporting information
p. 65 - 68
(2014/02/14)
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- Dicarboxylic Acid Derivatives and their Use
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The present application relates to novel dicarboxylic acid derivatives, process for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, es
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Page/Page column 15
(2010/03/02)
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- Tetrazole Derivatives and Their Use for the Treatment of Cardiovascular Diseases
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The present application relates to novel tetrazole derivatives, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, especial
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- Heterocyclic compounds with carboxyl isostere groups and their use for the treatment of cardiovascular diseases
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The present application relates to novel heterocyclic compounds, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, especia
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Page/Page column 33
(2009/09/25)
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- PYRROLOPYRIMIDINE DERIVATIVES USEFUL AS MODULATORS OF MULTIDRUG RESISTANCE
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A compound which is a pyrrolopyrimidine of formula (I) wherein: R1 is selected from R9 and halogen; R2 is NR6R7; R3 is selected from H, C1-C6 alkyl which is unsubstituted or substituted and -(CH2) nAr; R4 is selected from H, C1-C6 alkyl and -(CH2)? Ar; or R3 and R4 form, together with the N and C atoms to which they are attached, a fused five-, six-, seven- or eight-membered N-containing saturated ring which is unsubstituted or substituted; R5 is selected from CN, C02R9,C(O)NR10R11, -(CH2)nOH, -(CH2)nR10Rn, -C=CH, -C(S)NR10R11, -C(NH2)=NOR9, -C(R9)=NOR9, -C(NH2)NH, -C(O)R9 and an unsaturated 5- or 6-membered heterocyclic group which contains 1, 2 or 3 heteroatoms selected from N, O and S and which is unsubstituted or substituted; R6 and R7, which are the same or different, are selected from C1-C6 alkyl which is unsubstituted or substituted, -(CH2)nX and -(CH2)nAr; or R6 and R7 form, together with the nitrogen atom to which they are attached, a saturated five-, six-, seven- or eight-membered heterocyclic group which contains one nitrogen atom and 0 or from 1 to 3 additional heteroatoms selected from N, O and S, which is unsubstituted or substituted and which optionally contains one or two bridgehead atoms; R10and R11,which are the same or different, are selected from H, C1-C6 alkyl which is unsubstituted or substituted, -(CH2)nC3-C10 cycloalkyl and -(CH2)nAr; or R10 and R11 form, together with the nitrogen atom to which they are attached, a saturated five or six membered heterocyclic group which contains a nitrogen atom and 0 or from to 3 additional heteroatoms selected from O, S and N, which is unsubstituted or substituted and which is optionally fused to a benzene ring which is unsubstituted or substituted; n is the same or different when more than one is present within a given substituent group and is 0 or an integer of from 1 to 6; X is selected from -CN, -C02R9 and -NR10R11; R9 is the same or different when more than one is present within a given substituent group and is selected from -H, -QAr, -(CH2) nAr, C1-C6 alkyl which is unsubstituted or substituted and -(CH2) nC3-C10cycloalkyl, wherein the cycloalkyl moiety is optionally fused to a benzene ring which is unsubstituted or substituted; Q is C2-C6 alkenylene or alkynylene; and Ar is an unsaturated C6-C10 membered carbocyclic group or an unsaturated 5-11 membered heterocyclic group, which groups are unsubstituted or substituted; or a pharmaceutically acceptable salt thereof. These compounds have activity as inhibitors of MRP (multidrug resistant protein) and may thus be used to modulate multidrug resistance, for instance in potentiating the cytotoxicity of a chemotherapeutic agent.
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- Indoles
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A 1,4-substituted cyclic amine derivative represented by the following formula or a pharmacologically acceptable salt thereof: wherein A, B, C, D, T, Y, and Z each represent a methine or a nitrogen linkage; R1, R2, R3, R4, and R5 each represent a substituent; n represents 0 or an integer of 1 to 3; m represents 0 or an integer of 1 to 6; and p represents an integer of 1 to 3. The compounds have serotonin antagonism. They are therefore clinically useful as medicaments, in particular, for treating, ameliorating, and preventing spastic paralysis. They are also useful as central muscle relaxants for ameliorating myotonia.
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- ORTHO SUBSTITUTED AROMATIC COMPOUNDS USEFUL AS ANTAGONISTS OF THE PAIN ENHANCING EFFECTS OF E-TYPE PROSTAGLANDINS
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The invention relates to compounds of the formula (I): STR1 wherein A, B and D are various ring systems such as phenyl, R. sup.1 includes carboxy, R 3 is hydrogen or C 1-4 alkyl and Z is a linking group such as--(CH(R 5)) m--wherein m is 2, 3 or 4, and R 5 includes hydrogen and methyl; and pharmaceutically acceptable salts and in vivo hydrolysable esters or amides thereof, processes for preparing these compounds, pharmaceutical compositions comprising them, and their use in the treatment of pain.
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- Muscarinic receptor antagonists
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Compounds of the formula STR1 and the pharmaceutically acceptable salts thereof, wherein: Y is a direct link, --CH 2 --, --(CH 2) 2 --, --CH 2 O-- or --CH 2 S--; R is --CN or --CONH 2 ; and R 1 is STR2 where X and X 1 are each independently O or CH 2 ; and m is 1, 2 or 3, are muscarinic receptor antagonists useful in the treatment of diseases and conditions associated with the altered motility and/or tone of smooth muscle, such as irritable bowel syndrome.
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- Muscarinic receptor antagonists
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Muscarinic receptor antagonists of formula (I), and their pharmaceutically acceptable salts, wherein Y is --CH 2 --, --(CH 2) 2 --, --CH 2 O--, --(CH 2) 2 O-- or --CH 2 S--; R is --CH or --CONH 2 ; and R 1 is a group of formula (a), where R 2 and R 3 are each independently H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, --(CH 2) n OH, halo, trifluoromethyl, cyano, --(CH 2) n NR 4 R 5, --CO(C 1 -C 4 alkyl), --OCO(C 1 -C 4 alkyl), --CH(OH)(C 1 -C 4 alkyl), --C(OH)(C 1 -C 4 alkyl 2, --SO 2 NH 2, --(CH 2) n CONR 6 R 7 or --(CH 2) n COO(C 1 -C 4 alkyl); R 4 is H or C 1 -C 4 alkyl; R 5 is H, C 1 -C 4 alkyl or C 1 -C 4 alkysulphonyl; R 6 and R 7 are each independently H or C 1 -C 4 alkyl; and n is 0, 1 or 2. The compounds are particularly useful in treating irritable bowel syndrome.
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- Synthesis of 4-(4-Amidinophenyl)-2-arylsulphonylaminobutyric Acid Amides
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4-(4-Amidinophenyl)-2-arylsulphonylaminobutyric acid amides with differing amide and arylsulphonyl components were synthetized to test their inhibitory activity against serine proteinases.For the purpose of preparing these compounds, β-(4-cyanophenyl)ethylbromide (5) was reacted with acetaminomalonic acid diethyl ester to give 6, the acid hydrolysis of which yielded predominantly 4-(4-carbamoylphenyl)-2-aminobutyric acid (7).The simultaneously formed dicarboxylic acid 9 was separated after N-arylsulphonylation.The reaction of the N-arylsulphonylated acids 10-15 with thionyl chloride afforded acid chlorides (16-18) with a cyano function from which carboxylic acid amides (19-39) were obtained by reaction with diffrent amines.These compounds were converted into the hydroiodides of the compounds named in the title via the thioamides and the thioimidic acid ester hydroiodides.
- Wagner, G.,Vieweg, H.
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