- Design, synthesis and characterization of HIV-1 ca-targeting small molecules: Conformational restriction of PF74
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Small molecules targeting the PF74 binding site of the HIV-1 capsid protein (CA) confer potent and mechanistically unique antiviral activities. Structural modifications of PF74 could further the understanding of ligand binding modes, diversify ligand chemical classes, and allow identification of new variants with balanced antiviral activity and metabolic stability. In the current work, we designed and synthesized three series of PF74-like analogs featuring conformational constraints at the aniline terminus or the phenylalanine carboxamide moiety, and characterized them using a biophysical thermal shift assay (TSA), cell-based antiviral and cytotoxicity assays, and in vitro metabolic stability assays in human and mouse liver microsomes. These studies showed that the two series with the phenylalanine carboxamide moiety replaced by a pyridine or imidazole ring can provide viable hits. Subsequent SAR identified an improved analog 15 which effectively inhibited HIV-1 (EC50 = 0.31 μM), strongly stabilized CA hexamer (?Tm = 8.7?C), and exhibited substantially enhanced metabolic stability (t1/2 = 27 min for 15 vs. 0.7 min for PF74). Metabolic profiles from the microsomal stability assay also indicate that blocking the C5 position of the indole ring could lead to increased resistance to oxidative metabolism.
- Sahani, Rajkumar Lalji,Diana-Rivero, Raquel,Vernekar, Sanjeev Kumar V.,Wang, Lei,Du, Haijuan,Zhang, Huanchun,Castaner, Andres Emanuelli,Casey, Mary C.,Kirby, Karen A.,Tedbury, Philip R.,Xie, Jiashu,Sarafianos, Stefan G.,Wang, Zhengqiang
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Read Online
- Covalent Inhibition of Wild-Type HIV-1 Reverse Transcriptase Using a Fluorosulfate Warhead
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Covalent inhibitors of wild-type HIV-1 reverse transcriptase (CRTIs) are reported. Three compounds derived from catechol diether non-nucleoside inhibitors (NNRTIs) with addition of a fluorosulfate warhead are demonstrated to covalently modify Tyr181 of HIV-RT. X-ray crystal structures for complexes of the CRTIs with the enzyme are provided, which fully demonstrate the covalent attachment, and confirmation is provided by appropriate mass shifts in ESI-TOF mass spectra. The three CRTIs and six noncovalent analogues are found to be potent inhibitors with both IC50 values for in vitro inhibition of WT RT and EC50 values for cytopathic protection of HIV-1-infected human T-cells in the 5-320 nM range.
- Ippolito, Joseph A.,Niu, Haichan,Bertoletti, Nicole,Carter, Zachary J.,Jin, Shengyan,Spasov, Krasimir A.,Cisneros, José A.,Valhondo, Margarita,Cutrona, Kara J.,Anderson, Karen S.,Jorgensen, William L.
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supporting information
p. 249 - 255
(2021/01/26)
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- HISTONE ACETYLTRANSFERASE (HAT) INHIBITOR AND USE THEREOF
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The present invention relates to a histone acetyltransferase (HAT) inhibitor. Provided are a compound represented by general formula I, a pharmaceutically acceptable salt, a stereoisomer, an enantiomer, a diastereomer, an atropisomer, a racemate, a polymorph, a solvate or an isotope-labeled compound (including deuterium substitution) thereof, a preparation method therefor, a pharmaceutical composition comprising the same, and use thereof in the treatment of various HAT-related diseases or conditions.
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Paragraph 0544-0545
(2021/02/25)
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- COMBINATION TREATMENTS COMPRISING ADMINISTRATION OF 1H-PYRAZOLO[4,3-B]PYRIDINES
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The present invention provides 1H-pyrazolo[4,3-b]pyridin-7-amines of formula (I) as PDE1 inhibitors together with a second compound useful in the treatment of a neurodegenerative disorder and their combined use as a medicament, in particular for the treatment of neurodegenerative and/or cognitive disorders.
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Page/Page column 134
(2019/07/19)
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- 1H-PYRAZOLO[4,3-B]PYRIDINES AS PDE1 INHIBITORS
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The present invention provides 1H-pyrazolo[4,3-b]pyridines of formula (I) as PDE1 inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders.
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Paragraph 0635-0636
(2019/07/10)
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- COMBINATION TREATMENTS COMPRISING ADMINISTRATION OF 1H-PYRAZOLO[4,3-B]PYRIDINES
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The present invention provides 1H-pyrazolo[4,3-b]pyridin-7-amines of formula (I) as PDE1 inhibitors together with a second compound which compound is useful in the treatment of a psychiatric disorder and their combined use as a medicament, in particular for the treatment of psychiatric and/or cognitive disorders.
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Page/Page column 131
(2019/07/19)
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- Discovery of TRPM8 Antagonist (S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic Acid (AMG 333), a Clinical Candidate for the Treatment of Migraine
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Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in preclinical toxicology studies to identify a clinical candidate with an acceptable preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials.
- Horne, Daniel B.,Biswas, Kaustav,Brown, James,Bartberger, Michael D.,Clarine, Jeffrey,Davis, Carl D.,Gore, Vijay K.,Harried, Scott,Horner, Michelle,Kaller, Matthew R.,Lehto, Sonya G.,Liu, Qingyian,Ma, Vu V.,Monenschein, Holger,Nguyen, Thomas T.,Yuan, Chester C.,Youngblood, Beth D.,Zhang, Maosheng,Zhong, Wenge,Allen, Jennifer R.,Chen, Jian Jeffrey,Gavva, Narender R.
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p. 8186 - 8201
(2018/09/21)
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- 1H-PYRAZOLO[4,3-B]PYRIDINES AS PDE1 INHIBITORS
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The present invention provides 1H-pyrazolo[4,3-b]pyridin-7-amines of formula (I) as PDE1 inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders.
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Page/Page column 125
(2018/09/25)
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- Multi-substituted amine compound and its preparation and use (by machine translation)
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The invention belongs to the field of medical technology, in particular, the present invention provides the following formula I shown multi-substituted amine compound or its isomer or its pharmaceutically acceptable salt, ester, prodrug or hydrate, its pharmaceutical composition, preparation method thereof and its use in the preparation of medicine for treating aids in use. The compound or pharmaceutical composition containing the compound can be used as an inhibitor for inhibiting HIV integrase with LEDGF/p75 between protein - protein interaction and HIV integrase dimerization, then can be used for the treatment of aids. . (by machine translation)
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Paragraph 0687; 0691-0694
(2018/04/27)
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- IMIDAZOPYRIMIDINE COMPOUNDS USEFUL FOR THE TREATMENT OF CANCER
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A compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating a PRC2-mediated disease or disorder: wherein A, R3, R4, R6, and R7 are as defined herein.
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Paragraph 00170
(2018/04/12)
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- 6,5-BICYCLIC OCTAHYDROPYRROLOPYRIDINE OREXIN RECEPTOR ANTAGONISTS
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The present invention is directed to 6,5-bicyclic octahydropyrrolopyridine compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
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Page/Page column 46; 47
(2016/07/05)
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- METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS
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The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
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Page/Page column 36; 37
(2016/06/28)
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- ETHYLDIAMINE OREXIN RECEPTOR ANTAGONISTS
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The present invention is directed to ethyldiamne compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
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Page/Page column 47
(2016/07/05)
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- BRIDGED DIAZEPANE OREXIN RECEPTOR ANTAGONISTS
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The present invention is directed to bridged diazepane compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
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Page/Page column 44
(2016/06/14)
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- TRIAZOLOPYRIMIDINE COMPOUNDS AND USES THEREOF
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A compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating a PRC2-mediated disease or disorder: wherein R1, R2, R3, R4, R5, and n are as defined herein.
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Paragraph 0361; 0362
(2016/07/27)
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- Optimization of potency and pharmacokinetic properties of tetrahydroisoquinoline transient receptor potential melastatin 8 (TRPM8) antagonists
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Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system. TRPM8 is the predominant mammalian cold temperature thermosensor and is activated by cold temperatures ranging from 8 to 25 °C and cooling compounds such as menthol or icilin. TRPM8 antagonists are being pursued as potential therapeutics for treatment of pain and bladder disorders. This manuscript outlines new developments in the SAR of a lead series of 1,2,3,4-tetrahydroisoquinoline derivatives with emphasis on strategies to improve pharmacokinetic properties and potency. Selected compounds were profiled in two TRPM8 target-specific in vivo coverage models in rats (the icilin-induced wet dog shake model and the cold pressor test). Compound 45 demonstrated robust efficacy in both pharmacodynamic models with ED90 values 3 mg/kg.
- Horne, Daniel B.,Tamayo, Nuria A.,Bartberger, Michael D.,Bo, Yunxin,Clarine, Jeffrey,Davis, Carl D.,Gore, Vijay K.,Kaller, Matthew R.,Lehto, Sonya G.,Ma, Vu V.,Nishimura, Nobuko,Nguyen, Thomas T.,Tang, Phi,Wang, Weiya,Youngblood, Beth D.,Zhang, Maosheng,Gavva, Narender R.,Monenschein, Holger,Norman, Mark H.
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p. 2989 - 3004
(2014/05/06)
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- Synthesis and σ receptor affinity of regioisomeric spirocyclic furopyridines
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In order to investigate systematically the effect of the position of the pyridine N-atom on the σ1 receptor affinity four regioisomeric furopyridines 2a-d were synthesized and pharmacologically evaluated. The key steps of the synthesis comprise bromine/lithium exchange at regioisomeric bromopyridinecarbaldehyde acetals 7a-d, subsequent addition to 1-benzylpiperidin-4-one and cyclization. The regioisomeric acetals 7a-d were obtained either by o-metalation of bromopyridines 5b and 5c or by oxidation of bromopicolines 3a and 3d. In radioligand binding studies the regioisomeric furopyridines 2a-d showed 7- to 12-fold lower σ1 affinity than the benzofuran analog 1. The reduced σ1 affinity of the furopyridines 2a-d is explained with the reduced electron density of the pyridine ring. Since the four regioisomeric furopyridines show almost the same σ1 affinity (Ki = 4.9-10 nM), a directed interaction of the pyridine N-atom with the receptor protein can be excluded.
- Miyata, Kengo,Schepmann, Dirk,Wünsch, Bernhard
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p. 709 - 716
(2014/07/22)
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- Continuous flow magnesiation of functionalized heterocycles and acrylates with TMPMgCl·LiCl
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A flow procedure for the metalation of functionalized heterocycles (pyridines, pyrimidines, thiophenes, and thiazoles) and various acrylates using the strong, non-nucleophilic base TMPMgCl·LiCl is reported. The flow conditions allow the magnesiations to be performed under more convenient conditions than the comparable batch reactions, which often require cryogenic temperatures and long reaction times. Moreover, the flow reactions are directly scalable without further optimization. Metalation under flow conditions also allows magnesiations that did not produce the desired products under batch conditions, such as the magnesiation of sensitive acrylic derivatives. The magnesiated species are subsequently quenched with various electrophiles, thereby introducing a broad range of functionalities. Go with the flow: Flow conditions allow a practical metalation of functionalized heterocycles and various acrylates in the presence of the base TMPMgCl·LiCl (TMP=2,2,6,6-tetramethylpiperidyl). More convenient temperatures and very fast reaction times can usually be achieved by applying the flow conditions. Sensitive acrylic derivatives can be magnesiated under flow conditions. Furthermore, the flow reactions are readily scalable without further optimization.
- Petersen, Trine P.,Becker, Matthias R.,Knochel, Paul
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supporting information
p. 7933 - 7937
(2014/08/05)
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- TRPM8 ANTAGONISTS AND THEIR USE IN TREATMENTS
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Compounds of Formula (I) are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula (I) have the above structure, where the definitions of the variables are provided herein.
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Page/Page column 105
(2013/02/28)
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- TRPM8 ANTAGONISTS AND THEIR USE IN TREATMENTS
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Compounds of Formula (I) are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula (I) have a structure where the definitions of the variables are provided herein.
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Page/Page column 127-128
(2013/02/28)
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- Synthesis of the pyridinyl analogues of dibenzylideneacetone (pyr-dba) via an improved Claisen-Schmidt condensation, displaying diverse biological activities as curcumin analogues
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An efficient and easy procedure to synthesize the pyridinyl analogues of dibenzylideneacetone (pyr-dba) was developed by the condensation of substituted nicotinaldehyde and acetone in the presence of K2CO3 in toluene-EtOH-H2O solvent system. Structurally diverse pyr-dba, including quinolinyl dba, can be prepared conveniently in moderate to excellent yields under mild conditions with this method. The resulting pyr-dba functioned as the enone analogs of curcumin and efficiently inhibited the activation of NF-κB and the growth of colorectal carcinoma HCT116 p53+/+ cells as well as the HIV-1 IN-LEDGF/p75 interaction. The Royal Society of Chemistry 2012.
- Cao, Bin,Wang, Yong,Ding, Kan,Neamati, Nouri,Long, Ya-Qiu
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experimental part
p. 1239 - 1245
(2012/03/07)
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- The expedient access to bromo-pyridine carbaldehyde scaffolds using gem-dibromomethyl intermediates
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A simple, efficient, and general two-step synthesis to bromo-pyridine carbaldehyde scaffolds is described. This direct route involves sequential reactions employing the dibromination of bromo-picolines followed by hydrolysis using an aqueous solution of calcium carbonate. Bromo-pyridine carbaldehyde scaffolds 1-7 were obtained in good overall yield. Bromo-dibromomethyl-pyridine intermediates have been isolated and characterized.
- Mandal, Ashis Baran,Augustine, John Kallikat,Quattropani, Anna,Bombrun, Agnes
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p. 6033 - 6036
(2007/10/03)
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- INHIBITORS OF AKT ACTIVITY
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The present invention is directed to compounds which contain substituted napthyridines which inhibit the activity of Akt, a serine/threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention.
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Page/Page column 53-54
(2010/02/14)
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