- Synthesis and biological evaluation of benzhydryl-based antiplasmodial agents possessing Plasmodium falciparum chloroquine resistance transporter (PfCRT) inhibitory activity
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Due to the surge in resistance to common therapies, malaria remains a significant concern to human health worldwide. In chloroquine (CQ)-resistant (CQ-R) strains of Plasmodium falciparum, CQ and related drugs are effluxed from the parasite's digestive vacuole (DV). This process is mediated by mutant isoforms of a protein called CQ resistance transporter (PfCRT). CQ-R strains can be partially re-sensitized to CQ by verapamil (VP), primaquine (PQ) and other compounds, and this has been shown to be due to the ability of these molecules to inhibit drug transport via PfCRT. We have previously developed a series of clotrimazole (CLT)-based antimalarial agents that possess inhibitory activity against PfCRT (4a,b). In our endeavor to develop novel PfCRT inhibitors, and to perform a structure-activity relationship analysis, we synthesized a new library of analogues. When the benzhydryl system was linked to a 4-aminoquinoline group (5a-f) the resulting compounds exhibited good cytotoxicity against both CQ-R and CQ-S strains of P. falciparum. The most potent inhibitory activity against the PfCRT-mediated transport of CQ was obtained with compound 5k. When compared to the reference compound, benzhydryl analogues of PQ (5i,j) showed a similar activity against blood-stage parasites, and a stronger in vitro potency against liver-stage parasites. Unfortunately, in the in vivo transmission blocking assays, 5i,j were inactive against gametocytes.
- Relitti, Nicola,Federico, Stefano,Pozzetti, Luca,Butini, Stefania,Lamponi, Stefania,Taramelli, Donatella,D'Alessandro, Sarah,Martin, Rowena E.,Shafik, Sarah H.,Summers, Robert L.,Babij, Simone K.,Habluetzel, Annette,Tapanelli, Sofia,Caldelari, Reto,Gemma, Sandra,Campiani, Giuseppe
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supporting information
(2021/03/08)
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- Convenient Continuous Flow Synthesis of N-Methyl Secondary Amines from Alkyl Mesylates and Epoxides
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The first continuous flow process was developed to synthesize N-methyl secondary amines from alkyl mesylates and epoxides via a nucleophilic substitution using aqueous methylamine. A variety of N-methyl secondary amines were produced in good to excellent yields, including a number of bioactive compounds or their precursors. Up to 10.6 g (88% yield) of an N-methyl secondary amine was produced in 140 min process time. The amination procedure included an in-line workup, and the starting mesylate material was also produced in continuous flow from the corresponding alcohol. Finally, an in-line process combining the mesylate synthesis and nucleophilic substitution was developed.
- Lebel, Hélène,Mathieu, Gary,Patel, Heena
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supporting information
p. 2157 - 2168
(2020/11/23)
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- Enantioselective Copper(I)/Chiral Phosphoric Acid Catalyzed Intramolecular Amination of Allylic and Benzylic C?H Bonds
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Radical-involved enantioselective oxidative C?H bond functionalization by a hydrogen-atom transfer (HAT) process has emerged as a promising method for accessing functionally diverse enantioenriched products, while asymmetric C(sp3)?H bond amination remains a formidable challenge. To address this problem, described herein is a dual CuI/chiral phosphoric acid (CPA) catalytic system for radical-involved enantioselective intramolecular C(sp3)?H amination of not only allylic positions but also benzylic positions with broad substrate scope. The use of 4-methoxy-NHPI (NHPI=N-hydroxyphthalimide) as a stable and chemoselective HAT mediator precursor is crucial for the fulfillment of this transformation. Preliminary mechanistic studies indicate that a crucial allylic or benzylic radical intermediate resulting from a HAT process is involved.
- Ye, Liu,Tian, Yu,Meng, Xiang,Gu, Qiang-Shuai,Liu, Xin-Yuan
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supporting information
p. 1129 - 1133
(2019/12/12)
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- Modulators of the nuclear hormone receptor ROR
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The invention provides small molecule modulators of retinoic acid receptor-related orphan receptors such as RORα, RORβ, or RORγ, of formula with the variable atoms as defined herein and R1 comprising a hydroxyl- or alkoxyl-substituted fluoroalkyl group. Compounds of the invention can be effective modulators at concentrations ineffective to act on LXR receptors, or on other nuclear receptors, or other biological targets. Methods of modulation the RORs and methods of treating metabolic disorders, immune disorders, cancer, and CNS disorders wherein modulation of an ROR is medically indicated are also provided.
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Page/Page column 155
(2017/03/28)
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- Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153)
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Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical
- Bradbury, Robert H.,Callis, Rowena,Carr, Gregory R.,Chen, Huawei,Clark, Edwin,Feron, Lyman,Glossop, Steve,Graham, Mark A.,Hattersley, Maureen,Jones, Chris,Lamont, Scott G.,Ouvry, Gilles,Patel, Anil,Patel, Joe,Rabow, Alfred A.,Roberts, Craig A.,Stokes, Stephen,Stratton, Natalie,Walker, Graeme E.,Ward, Lara,Whalley, David,Whittaker, David,Wrigley, Gail,Waring, Michael J.
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p. 7801 - 7817
(2016/10/22)
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- A PROCESS FOR THE PREPARATION OF A DERIVATIVE OF 2-METHYL-2'-PHENYLPROPIONIC ACID USING NEW INTERMEDIATES
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The present invention deals with a preparation method of derivatives of methyl-2 '- phenylpropionic acid, e.g. the antihistamine bilastine of formula 9 that uses a new intermediate of formula 27 in the form of a base or salt. The intermediate reacts with
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Page/Page column 12
(2014/03/22)
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- AZOLE DERIVATIVE
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The present invention provides agents for treating or preventing diseases such as mood disorder, anxiety disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal disease, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, immune-related disease, alopecia, and so forth. Specifically, the invention provides azole derivatives represented by general formula (I), or pharmaceutically acceptable salts thereof that have an antagonistic action against the arginine-vasopressin (AVP) V1b receptor:
- -
-
Paragraph 0274; 0275
(2014/09/17)
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- Traceless Staudinger acetylation of azides in aqueous buffers
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In this paper, we demonstrate the applicability of water-soluble p-dimethylaminoethyl substituted phosphinomethanethiol in acetyl transfer reactions by the traceless Staudinger ligation with unprotected *-azido lysine containing peptides in aqueous buffer systems. Additionally, we present an improved synthesis pathway for the water-soluble phosphinothiol linkers requiring less steps in a comparable overall yield in comparison to previously published protocols.
- Sowa, Sylwia,Mühlberg, Michaela,Pietrusiewicz, K. Michal,Hackenberger, Christian P.R.
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p. 3465 - 3472
(2013/07/11)
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- Water-soluble phosphinothiol reagents
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Water soluble reagents and methods for the formation of an amide bond between a phosphinothioester and an azide in an aqueous medium. The phosphinothioester is generated using a water-soluble phosphinothiol reagent. This reaction allows formation of an amide bond between a wide variety of chemical species including amino acids, peptides or protein fragments in an aqueous solution. Of particular interest, this reaction allows for the formation of an amide bond in a physiological setting. In a specific embodiment, this invention provides reagents and methods for peptide ligation in an aqueous medium. The reaction eliminates the need for a cysteine residue and is traceless leaving no residual atoms in the ligated peptide product.
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Page/Page column 25; 32
(2013/04/13)
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- 1, 2, 4-TRIAZOLONE DERIVATIVE
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The present invention provides a 1,2,4-triazolone derivative represented by Formula (1A) having an antagonistic activity on the arginine-vasopressin 1b receptor or a pharmaceutically acceptable salt thereof and provides a pharmaceutical composition comprising the compound or the salt as an active ingredient, in particular, a therapeutic or preventive agent exhibiting favorable pharmacokinetics in a disease such as mood disorder, anxiety disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal disease, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, immune-related disease, or alopecia.
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Paragraph 0586
(2013/08/14)
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- Identification of biaryl sulfone derivatives as antagonists of the histamine H3 receptor: Discovery of (R)-1-(2-(4′-(3- methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine (APD916)
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The design of a new clinical candidate histamine-H3 receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by re
- Semple, Graeme,Santora, Vincent J.,Smith, Jeffrey M.,Covel, Jonathan A.,Hayashi, Rena,Gallardo, Charlemagne,Ibarra, Jason B.,Schultz, Jeffrey A.,Park, Douglas M.,Estrada, Scott A.,Hofilena, Brian J.,Smith, Brian M.,Ren, Albert,Suarez, Marissa,Frazer, John,Edwards, Jeffrey E.,Hart, Ryan,Hauser, Erin K.,Lorea, Jodie,Grottick, Andrew J.
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scheme or table
p. 71 - 75
(2012/02/16)
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- Removal of sphingosine 1-phosphate receptor-3 (S1P3) agonism is essential, but inadequate to obtain immunomodulating 2-aminopropane-1,3-diol S1P1 agonists with reduced effect on heart rate
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A series of 2-substituted 2-aminopropane-1,3-diols having a biphenyl moiety and their phosphate esters were synthesized to obtain sphingosine 1-phosphate receptor-1 (S1P1) receptor agonists with potent immunomodulatory activity accompanied by little or no effect on heart rate. Many of the synthesized compounds sufficiently decreased the number of peripheral blood lymphocytes. Some of the phosphates had potent agonism at S1P1 but no agonism at S1P3, which had been reported to be a receptor responsible for heart rate reduction. Although high S1P1/S1P 3 selectivity was considered to be favorable to reduce the effect on heart rate, almost all the phosphates showed a remarkable heart rate lowering effect in vivo. The results suggest that other factors in addition to S1P 3 agonism should be responsible for the heart rate reduction caused by S1P1 agonists. Only 2-amino-2-[2-[2′-fluoro-4′-(4- methylphenylthio)biphenyl-4-yl]ethyl]propane-1,3-diol (6d) was identified as a desired S1P1 receptor agonist having both the immunomodulatory activity and an attenuated effect on heart rate by a unique screening flow using in vivo evaluating systems primarily.
- Hamada, Maiko,Nakamura, Mitsuharu,Kiuchi, Masatoshi,Marukawa, Kaoru,Tomatsu, Ayumi,Shimano, Kyoko,Sato, Noriko,Sugahara, Kunio,Asayama, Mahoko,Takagi, Kan,Adachi, Kunitomo
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experimental part
p. 3154 - 3168
(2010/10/03)
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- MODULATORS OF THE HISTAMINE H3 RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
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Amide derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the histamine H3 receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of histamine H3-associated disorders, such as cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as excessive daytime sleepiness, narcolepsy, shift-work sleep disorder, drowsiness as a side effect from a medication, maintenance of vigilance to aid in the completion of tasks and the like, cataplexy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia, Alzheimer's disease, pain and the like.
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Page/Page column 98
(2009/10/18)
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- Design and evaluation of novel biphenyl sulfonamide derivatives with potent histamine H3 receptor inverse agonist activity
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Antagonism of the histamine-H3 receptor is one tactic being explored to increase wakefulness for the treatment of disorders such as excessive daytime sleepiness (EDS) as well as other sleep or cognitive disorders. Phenethyl-R-2-methylpyrrolidin
- Covel, Jonathan A.,Santora, Vincent J.,Smith, Jeffrey M.,Hayashi, Rena,Gallardo, Charlemagne,Weinhouse, Michael I.,Ibarra, Jason B.,Schultz, Jeffrey A.,Park, Douglas M.,Estrada, Scott A.,Hofilena, Brian J.,Pulley, Michelle D.,Smith, Brian M.,Ren, Albert,Suarez, Marissa,Frazer, John,Edwards, Jeffrey,Hauser, Erin K.,Lorea, Jodie,Semple, Graeme,Grottick, Andrew J.
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experimental part
p. 5603 - 5611
(2010/02/28)
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- DIAZACARBAZOLES AND METHODS OF USE
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The invention relates to 1,7-diazacarbazole compounds of Formula (I), (I-a) and (I-b) which are useful as kinase inhibitors, more specifically useful as checkpoint kinase 1 (chkl) inhibitors, thus useful as cancer therapeutics. The invention also relates to compositions, more specifically pharmaceutical compositions comprising these compounds and methods of using the same to treat various forms of cancer and hyperproliferative disorders, as well as methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.
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Page/Page column 147-148
(2010/01/07)
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- MODULATORS OF THE HISTAMINE H3-RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
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The present invention relates to certain biphenyl sulfonamide derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the histamine H3-receptor. Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of histamine H3-receptor associated disorders, such as, cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia, Alzheimer's disease and the like.
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Page/Page column 62-63
(2008/06/13)
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- BIPHENYL SULFONYL AND PHENYL-HETEROARYL SULFONYL MODULATORS OF THE HISTAMINE H3-RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
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The present invention relates to certain biphenyl sulfonamide derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the histamine H3- receptor. Compounds of the present invention and pharmaceutical compositions
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Page/Page column 53-54
(2008/12/05)
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- Novel H3 receptor antagonists with improved pharmacokinetic profiles
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A new series of H3 antagonists derived from the natural product Conessine are presented. Several compounds from these new series retain the potency and selectivity of earlier diamine based analogs while exhibiting improved PK characteristics. O
- Santora, Vincent J.,Covel, Jonathan A.,Hayashi, Rena,Hofilena, Brian J.,Ibarra, Jason B.,Pulley, Michelle D.,Weinhouse, Michael I.,Semple, Graeme,Ren, Albert,Pereira, Guilherme,Edwards, Jeffrey E.,Suarez, Marissa,Frazer, John,Thomsen, William,Hauser, Erin,Lorea, Jodie,Grottick, Andrew J.
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scheme or table
p. 4133 - 4136
(2009/05/30)
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- Water-soluble phosphinothiols for traceless Staudinger ligation and integration with expressed protein ligation
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The traceless Staudinger ligation is an effective means to synthesize an amide bond between two groups of otherwise orthogonal reactivity: a phosphinothioester and an azide. An important application of the Staudinger ligation is in the ligation of peptide
- Tam, Annie,Soellner, Matthew B.,Raines, Ronald T.
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p. 11421 - 11430
(2008/03/14)
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- BI-ARYL COMPOUND HAVING IMMUNOSUPPRESSIVE ACTIVITY
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The invention is directed to a bi-aryl compound having a unique immunomodulating activity, a process for a preparation thereof, a pharmaceutical composition containing the same, and a method of preventing or treating disorders or diseases mediated by T lymphocytes by administering the compound to a subject in need of treatment.
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Page/Page column 43; 44
(2010/02/10)
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- Synthesis of radioiodine-labeled 2-phenylethyl 1-thio-β-D-galactopyranoside for imaging of LacZ gene expression
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A potent inhibitor of β-galactosidase (EC 3.2.1.23), 2-phenylethyl 1-thio-β-D-galactopyranoside (PETG), was radioiodinated for noninvasive imaging of LacZ gene expression. In order to introduce radioiodine to the phenyl ring of PETG, 2-(4-bromophenyl)ethanethiol was prepared and attached to the C-1 position of β-D-galactose pentaacetate under conditions that resulted in the exclusive formation of the β anomer. The bromo group of PETG was converted to the tributylstannyl group where radioiododemetallation was carried out. Radioiodine-labeled PETG tetraacetate was purified by HPLC, which can be used as a prodrug for biological evaluation or hydrolyzed to 2-(4-[123I/125I]iodophenyl)ethyl 1-thio-β-D-galactopyranoside ([123I/125I]7) under basic conditions. The resulting radioiodine-labeled PETG was obtained in overall 62% radiochemical yield (decay-corrected) and with specific activity of 46-74 GBq/μmol.
- Choi, Joon Hun,Choe, Yearn Seong,Lee, Kyung-Han,Choi, Yong,Kim, Sang Eun,Kim, Byung-Tae
-
-
- Parallel-compound synthesis: Methodology for accelerating drug discovery
-
Parallel compound synthesis enables large numbers of individual compounds to be prepared simultaneously using semiautomated techniques. This fast and efficient methodology has an important role to play in accelerating lead optimisation and hence the whole drug discoveIy process. The potential of this strategy to rapidly optimise chemical leads an.d provide structureactivity relationship (SAR) information was demonstrated in two therapeutic areas, antiviral agents (herpes simplex virus), and neurokinin-2 receptor antagonists.
- Selway, Christopher N.,Terrett, Nicholas K.
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p. 645 - 654
(2007/10/03)
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- Synthesis of (+/-)--9-halogeno-2-methyl-1,2,3,4,4a,5,6,10b,11,12,12a-dodecahydronaphthoisoquinolines
-
Treatment of 5-(2-arylethyl)-1,2,3,4,5,6,7,8-octahydroisoquinolines with 48percent HBr resulted in isomerisation of the double bond and subsequent cyclisation at position 6 of the octahydroisoquinoline ring system to give (+/-)--9-halogeno-2-methyl-1,2,3,4,4a,4b,5,6,10b,11,12,12a-dodecahydronaphtho2,1-f>isoquinolines.The products obtained represent novel analogues of aza-D-homoestranes.No reaction was observed with the corresponding 5,5-disubstituted octahydroisoquinolines.An X-ray crystallographic study of compound 10 (X = Br) is described.
- Patrick, Graham L.
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p. 1273 - 1280
(2007/10/02)
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- Peripherally Acting Enkephalin Analogues. 2. Polar Tri- and Tetrapeptides
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The design, synthesis, and biological activity of a series of -Arg2-enkephalin-derived tetrapeptide amides and tripeptide aralkylamides are reported.These polar analogues were designed to be excluded from the central nervous system with their action thus limited to peripheral opioid receptors.The effects of the nature of the aromatic ring, aryl ring substitution, and aralkylamine chain length on activity were investigated; in a number of cases the N-terminal amino group of Tyr1 was converted to a guanidino group to further increase hydrophilicity.The peptides were all synthesized by classical solution methodology.The opioid activit y of the peptides was assessed in vitro on the guinea pig ileum and their antinociceptive activity was determined in vivo in chemically induced writhing models (peripheral activity) and in the hot-plate test (central activity), in rodents.That the analgesic effects were predominantly mediated in the periphery was demonstrated by antagonism of antinociception by the peripheral opioid antagonist N-methylnalorphine and by comparison of the activities in the writhing and hot-plate tests.As a class, the tetrapeptides were more potent than the tripeptides; Nα-amidination generally increased activity.A number of compounds exhibited very potent opioid activity and had the desired pharmacological profile, indicating a high degree of peripheral selectivity.
- Hardy, George W.,Lowe, Lawrence A.,Mills, Gail,Sang, Pang Yih,Simpkin, Dean S. A.,et al.
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p. 1108 - 1118
(2007/10/02)
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