- A "two-Birds-One-Stone" Approach toward the Design of Bifunctional Human Immunodeficiency Virus Type 1 Entry Inhibitors Targeting the CCR5 Coreceptor and gp41 N-Terminal Heptad Repeat Region
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Previous studies have reported the stepwise nature of human immunodeficiency virus type 1 (HIV-1) entry and the pivotal role of coreceptor CCR5 and the gp41 N-terminal heptad repeat (NHR) region in this event. With this in mind, we herein report a dual-targeted drug compound featuring bifunctional entry inhibitors, consisting of a piperidine-4-carboxamide-based CCR5 antagonist, TAK-220, and a gp41 NHR-targeting fusion-inhibitory peptide, C34. The resultant chimeras were constructed by linking both pharmacophores with a polyethylene glycol spacer. One chimera, CP12TAK, exhibited exceptionally potent antiviral activity, about 40- and 306-fold over that of its parent inhibitors, C34 and TAK-220, respectively. In addition to R5-tropic viruses, CP12TAK also strongly inhibited infection of X4-tropic HIV-1 strains. These data are promising for the further development of CP12TAK as a new anti-HIV-1 drug. Results show that this strategy could be extended to the design of therapies against infection of other enveloped viruses.
- Wang, Chao,Wang, Xinling,Wang, Huan,Pu, Jing,Li, Qing,Li, Jiahui,Liu, Yang,Lu, Lu,Jiang, Shibo
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p. 11460 - 11471
(2021/08/03)
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- IMIDAZO [2, 1-F] [1, 2, 4] TRIAZIN-4-AMINE DERIVATIVES AS TLR7 AGONIST
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Disclosed herein is an imidazo [2, 1-f] [1, 2, 4] triazin-4-amine derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof useful as a TLR7 agonist, and a pharmaceutical composition comprising the same. Also disclosed herein is a method of treating cancer using the imidazo [2, 1-f] [1, 2, 4] triazin-4-amine derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as TLR7 agonist.
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Paragraph 0369-0370
(2020/08/22)
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- HISTONE DEACETYLASE INHIBITORS
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Provided herein are compounds and methods for inhibiting histone deacetylase ("HDAC") enzymes (e.g., HDAC1, HDAC2, and HDAC3).
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Paragraph 00256; 00258; 00276; 00278; 00319
(2018/07/29)
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- Benzamide capped peptidomimetics as non-ATP competitive inhibitors of CDK2 using the REPLACE strategy
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Inhibition of cyclin dependent kinase 2 (CDK2) in complex with cyclin A in G1/S phase of the cell cycle has been shown to promote selective apoptosis of cancer cells through the E2F1 pathway. An alternative approach to catalytic inhibition is to target the substrate recruitment site also known as the cyclin binding groove (CBG) to generate selective non-ATP competitive inhibitors. The REPLACE strategy has been applied to identify fragment alternatives and substituted benzoic acid derivatives were evaluated as a promising scaffold to present appropriate functionality to mimic key peptide determinants. Fragment Ligated Inhibitory Peptides (FLIPs) are described which potently inhibit both CDK2/cyclin A and CDK4/cyclin D1 and have preliminary anti-tumor activity. A structural rationale for binding was obtained through molecular modeling further demonstrating their potential for further development as next generation non ATP competitive CDK inhibitors.
- Premnath, Padmavathy Nandha,Craig, Sandra N.,Liu, Shu,McInnes, Campbell
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p. 3754 - 3760
(2016/07/22)
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- Tuned-affinity bivalent ligands for the characterization of opioid receptor heteromers
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Opioid receptors, including the μ- and δ-opioid receptors (MOR and DOR), are important targets for the treatment of pain. Although there is mounting evidence that these receptors form heteromers, the functional role of the MOR/DOR heteromer remains unresolved. We have designed and synthesized bivalent ligands as tools to elucidate the functional role of the MOR/DOR heteromer. Our ligands (L2 and L4) are comprised of a compound with low affinity at the DOR tethered to a compound with high affinity at the MOR, with the goal of producing ligands with "tuned affinity" at MOR/DOR heteromers as compared to DOR homomers. Here, we show that both L2 and L4 demonstrate enhanced affinity at MOR/DOR heteromers as compared to DOR homomers, thereby providing unique pharmacological tools to dissect the role of the MOR/DOR heteromer in pain.
- Harvey, Jessica H.,Long, Darcie H.,Whistler, Jennifer L.,England, Pamela M.
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p. 640 - 644,5
(2020/08/31)
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- MULTI-RING COMPOUNDS AND USES THEREOF
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Chemical agents, such as derivatives of hydroxy benzene moieties, and similar heterocyclic ring structures, including salts thereof, that act as anti-cancer and anti-tumor agents, especially where such agents modulate the activity of enzymes and structura
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Page/Page column 45
(2008/12/08)
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- Discovery of a piperidine-4-carboxamide CCR5 antagonist (TAK-220) with highly potent anti-HIV-1 activity
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We incorporated various polar groups into previously described piperidine-4-carboxamide CCR5 antagonists to improve their metabolic stability in human hepatic microsomes. Introducing a carbamoyl group into the phenyl ring of the 4-benzylpiperidine moiety
- Imamura, Shinichi,Ichikawa, Takashi,Nishikawa, Youichi,Kanzaki, Naoyuki,Takashima, Katsunori,Niwa, Shinichi,Iizawa, Yuji,Baba, Masanori,Sugihara, Yoshihiro
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p. 2784 - 2793
(2007/10/03)
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- DIARYLMETHYLIDENE PIPERIDINE DERIVATIVES, PREPARATIONS THEREOF AND USES THEREOF
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Compounds of formula: wherein R1, R2, and R3 are as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in p
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Page/Page column 21; 33
(2010/02/12)
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- DIARYLMETHYLIDENE PIPERIDINE DERIVATIVES, PREPARATIONS THEREOF AND USES THEREOF
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Compounds of Formula: wherein R1, R2, and R3 are as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in p
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Page/Page column 18; 29-30
(2010/02/12)
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- DIARYLMETHYLIDENE PIPERIDINE DERIVATIVES, PREPARATIONS THEREOF AND USES THEREOF
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Compounds of general formula: wherein R1, R2, R3, R4, and R5 are as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compounds are prep
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- PHENYL-PIPERIDIN-4-YLIDENE-METHYL-BENZAMIDE DERIVATIVES FOR THE TREATMENT OF PAIN OR GASTROINTESTINAL DISORDERS
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Compounds of general formula: wherein R1, R2 and R3 are as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.
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- 4-{`3-(SULFONYLAMINO) PHENYL! `1-(CYCLYMETHYL) PIPERIDIN-4-YLIDENE! METHYL} BENAZMIDE DERIVATIVES AS DELTA OPIOID RECEPTOR LIGANDS FOR THE TREATMENT OF PAIN, ANXIETY AND FUNCTIONAL GASTROINTESTINAL DISORDER
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Compounds of general formula: (I) wherein R1,R2, R3, R4 and R5 are as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compounds
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- DIARYLMETHYLIDENE PIPERIDINE DERIVATIVES, PREPARATIONS THEREOF AND USES THEREOF
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Compounds of general formula (I) wherein R1, R2, R3, R4, R5, R6, R7, m and n are as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in pa
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- DIARYLMETHYLIDENE PIPERIDINE DERIVATIVES, PREPARATIONS THEREOF AND USES THEREOF
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Compounds of general formula: Formula (I) wherein R1, R2, R3 and A are as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compounds are prepared. They are u
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- DIARYLMETHYLIDENE PIPERIDINE DERIVATIVES AND THEIR USE AS DELTA OPIOD RECEPTOR AGONISTS
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Compounds of general formula: (Formula (I)) wherein R1, R2, R3, R4 and R5 are as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compo
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-
- DIARYLMETHYLIDENE PIPERIDINE DERIVATIVES, PREPARATIONS THEREOF AND USES THEREOF
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Compounds of general formula: Formula (I) wherein R1, R2, R3 and R4 are as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.
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Page 18; 31-32
(2010/02/09)
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- DIARYLMETHYLIDENE PIPERIDINE DERIVATIVES, PREPARATIONS THEREOF AND USES THEREOF
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Compounds of formula: (I) wherein R1, R2, R3, R4 and R7 are as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compounds are prepared.
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Page 31; 50-51
(2010/02/09)
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- DIARYLMETHYLIDENE PIPERIDINE DERIVATIVES, PREPARATIONS THEREOF AND USES THEREOF AS OPIOID RECEPTORS LIGANDS
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Compounds of general formula: (I) wherein R1, R2, R3 and A are as defined in the specification, as well as salts, enantiomers thereof and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the treatment of pain and anxiety.
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- Cyclic amine compounds as CCR5 antagonists
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A compound of formula (I) (wherein R1is a hydrogen atom, a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, R2is a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, or R1and R2may combine to each other together with A to form a heterocyclic group which may be substituted; A is N or N+—R5.Y?(R5is a hydrocarbon group; Y?is a counter anion); R3is a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; n is 0 or 1; R4is a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an alkoxy group which may be substituted, an aryloxy group which may be substituted, or an amino group which may be substituted, E is a divalent aliphatic hydrocarbon group which may be substituted by group(s) other than oxo; G1is a bond, CO or SO2; G2is CO, SO2, NHCO, CONH or OCO; J is methine or a nitrogen atom; and each of Q and R is a bond or a divalent C1-3aliphatic hydrocarbon which may be substituted; provided that J is methine when G2is OCO, that one of Q and R is not a bond when the other is a bond and that each of Q and R is not substituted by oxo group(s) when G1is a bond) or a salt thereof has a potent CCR5 antagonistic activity and can be advantageously used for the treatment or prevention of infectious disease of various HIV in human (e.g. AIDS).
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- Hydroxyphenyl-piperidin-4-ylidene-methyl-benzamide derivatives for the treatment of pain
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Compounds of general formula I R1 is selected from any one of phenyl, pyridinyl, thienyl, furanyl, imidazolyl, triazolyl and thiazolyl; where each R1 phenyl ring and R1 heteroaromatic ring may optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched C1-C6 alkyl, NO2, CF3, C1-C6 alkoxy, chloro, fluoro, bromo, and iodo. The substitutions on the phenyl ring and on the heteroaromatic ring may take place in any position on said ring systems; are disclosed and claimed in the present application, as well as salts and pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain.
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- Quinolinyl-piperidin-4-ylidene-methyl-benzamide derivatives for the treatment of pain
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Compounds of general formula (I), where R1 is selected from any one of phenyl, pyridinyl, thienyl, furanyl, imidazolyl, and triazolyl; where each R1 phenyl ring and R1 heteroaromatic ring may optionally and independently b
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- UREA COMPOUNDS, PROCESS FOR PRODUCING THE SAME AND USE THEREOF
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A compound of the formula: [whereinR1 is a hydrocarbon group which may be substituted;R2 is a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;R3 is halogen atoms, a carbam
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- Compounds with analgesic effect
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Compounds of general formula (I) are disclosed and claimed in the present application, as well as their pharmaceutically acceptable salts, pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain.
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- BENZAMIDINE DERIVATIVES
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Benzamidine derivatives of the following formulae or analogs thereof, i. e., pharmaceutically acceptable salts thereof, are provided. These compounds or salts thereof have a blood-coagulation inhibiting effect based on an excellent effect of inhibiting the action of activated blood coagulation factor X, and they are useful as anticoagulants.
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- N,N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: A novel, exceptionally selective, potent δ opioid receptor agonist with oral bioavailability and its analogues
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The design, synthesis, and pharmacological evaluation of a novel class of δ opioid receptor agonists, N,N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (6a) and its analogues, are described. These compounds, formally derived from SNC-80 (2) by repl
- Wei,Brown,Takasaki,Plobeck,Delorme,Zhou,Yang,Jones,Gawell,Gagnon,Schmidt,Yue,Walpole,Payza,St-Onge,Labarre,Godbout,Jakob,Butterworth,Kamassah,Morin,Projean,Ducharme,Roberts
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p. 3895 - 3905
(2007/10/03)
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