- Synthesis of a Bicyclic Azetidine with in Vivo Antimalarial Activity Enabled by Stereospecific, Directed C(sp3)-H Arylation
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The development of new antimalarial therapeutics is necessary to address the increasing resistance to current drugs. Bicyclic azetidines targeting Plasmodium falciparum phenylalanyl-tRNA synthetase comprise one promising new class of antimalarials, especially due to their activities against three stages of the parasite's life cycle, but a lengthy synthetic route to these compounds may affect the feasibility of delivering new therapeutic agents within the cost constraints of antimalarial drugs. Here, we report an efficient synthesis of antimalarial compound BRD3914 (EC50 = 15 nM) that hinges on a Pd-catalyzed, directed C(sp3)-H arylation of azetidines at the C3 position. This newly developed protocol exhibits a broad substrate scope and provides access to valuable, stereochemically defined building blocks. BRD3914 was evaluated in P. falciparum-infected mice, providing a cure after four oral doses.
- Maetani, Micah,Zoller, Jochen,Melillo, Bruno,Verho, Oscar,Kato, Nobutaka,Pu, Jun,Comer, Eamon,Schreiber, Stuart L.
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supporting information
p. 11300 - 11306
(2017/08/21)
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- Mechanistic interrogation of the asymmetric lithiation-trapping of N-thiopivaloyl azetidine and pyrrolidine
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A fundamental mechanistic study of the s-BuLi/chiral diamine-mediated lithiation-trapping of N-thiopivaloyl azetidine and pyrrolidine is reported. We show that lithiated thiopivalamides are configurationally unstable at -78 °C. Reaction then proceeds via a dynamic resolution of diastereomeric lithiated intermediates and this accounts for the variable sense and degree of asymmetric induction observed compared to N-Boc heterocycles.
- Rayner, Peter J.,Smith, Joshua C.,Denneval, Charline,O'Brien, Peter,Clarke, Paul A.,Horan, Richard A. J.
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supporting information
p. 1354 - 1357
(2016/01/25)
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- Nickel-mediated radioiodination of aryl and heteroaryl bromides: Rapid synthesis of tracers for SPECT imaging
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Rapid and efficient radioiodination of aryl and heteroaryl bromides has been achieved using a nickel(0)-mediated halogen-exchange reaction. This transformation gives direct access to [123I]- and [ 125I]-imaging agents for single photon emission computed tomography (SPECT), such as 5-[123I]-A85380 (see scheme, Boc=tert- butyloxycarbonyl, cod=1,5-cyclooctadiene, TFA=trifluoroacetic acid). Copyright
- Cant, Alastair A.,Champion, Sue,Bhalla, Rajiv,Pimlott, Sally L.,Sutherland, Andrew
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supporting information
p. 7829 - 7832
(2013/08/23)
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- ISATIN ANALOGUES AND USES THEREFOR
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Novel isatin analogues, including isatin analogues comprising Michael Acceptors (IMAs) are disclosed. Further disclosed are methods of synthesis of the isatin analogues, and uses of the analogues, including inhibition of caspase-3 and caspase-7, and in vi
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Page/Page column 11
(2009/04/24)
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- Aminoacyl-tRNA synthetase inhibitors as potent and synergistic immunosuppressants
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The aminoacyl-tRNA synthetase family of enzymes is the target of many antibacterials and inhibitors of eukaryotic hyperproliferation. In screening analogues of 5′-O-(N-L-aminoacyl)-sulfamoyladenosine containing all 20 proteinogenic amino acids, we found t
- Van De Vijver, Pieter,Ostrowski, Tomasz,Sproat, Brian,Goebels, Jozef,Rutgeerts, Omer,Van Aerschot, Arthur,Waer, Mark,Herdewijn, Piet
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experimental part
p. 3020 - 3029
(2009/04/07)
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- Vanilloid receptor ligands and their use in treatments
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Compounds having the general structure and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.
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Page/Page column 55
(2008/06/13)
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- N-benzylisatin sulfonamide analogues as potent caspase-3 inhibitors: Synthesis, in vitro activity, and molecular modeling studies
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A number of isatin sulfonamide analogues were prepared and their potencies for inhibiting caspase-1, -3, -6, -7, and -8 were evaluated in vitro. Several compounds displaying a nanomolar potency for inhibiting the executioner caspases, caspase-3 and caspas
- Chu, Wenhua,Zhang, Jun,Zeng, Chenbo,Rothfuss, Justin,Tu, Zhude,Chu, Yunxiang,Reichert, David E.,Welch, Michael J.,Mach, Robert H.
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p. 7637 - 7647
(2007/10/03)
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- PROCESS FOR PRODUCING OPTICALLY ACTIVE AZETIDINE-2-CARBOXYLIC ACID
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The present invention provides an efficient, simple, and commercially advantageous process for producing optically active azetidine-2-carboxylic acid, which is an important material for medicines. The process includes the steps of halogenating an optically active N-protected 4-amino-2-hydroxybutyric acid following inversion of the configuration to produce an optically active N-protected 4-amino-2-halobutyryl halide; hydrolyzing the halide; deprotecting the amino group of the hydrolyzed product to produce an optically active 4-amino-2-halobutyric acid; cyclizing the product in an alkaline aqueous solution; and then protecting the amino group of the cyclized product to produce an optically active N-protected azetidine-2-carboxylic acid. The present invention also provides an optically active N-protected 4-amino-2-halobutyryl halide represented by general formula (2): (wherein P represents a protective group for the primary amino group; * indicates that the carbon atom is asymmetric; and each of X and Y independently represents a halogen atom), which is useful for producing the optically active azetidine-2-carboxylic acid.
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- Inhibitors of α4β1 mediated cell adhesion
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The present invention relates to compound of formula (I), that are potent inhibitors of α4β1mediated adhesion to either VCAM or CS-1 and which could be useful for the treatment of inflammatory diseases. Specifically, the molecules of the present invention can be used for treating or preventing α4β1adhesion mediated conditions in a mammal such as a human. This method may comprise administering to a mammal or a human patient an effective amount of the compound or composition as explained in the present specification.
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Page/Page column 144
(2010/02/05)
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- α-substituted hydroxamic acids as novel bacterial deformylase inhibitor-based antibacterial agents
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We report the synthesis and biological activity of analogues of VRC3375 (N-hydroxy-3-R-butyl-3-[(2-S-(tert-butoxycarbonyl)-pyrrolidin-1-ylcarbonyl] propionamide), an orally active peptide deformylase inhibitor. This study explores the structure-activity relationship of various chelator groups, alpha substituents, P2′ and P3′ substituents in order to achieve optimal antibacterial activity with minimal toxicity liability.
- Jain,Sundram,Lopez,Neckermann,Wu,Hackbarth,Chen,Wang,Ryder,Weidmann,Patel,Trias,White,Yuan
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p. 4223 - 4228
(2007/10/03)
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- PROCESS FOR THE REMOVAL OF NITROBENZENESULFONYL
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A 2- or 4-nitrobenzenesulfonamide is allowed to react with an alkali metal alkoxide to remove a nitrobenzenesulfonyl group to thereby obtain an amine corresponding to the amide. Furthermore, a method for producing an amine derivative by allowing the resulting amine without isolation to react with an activated, substituted oxycarbonyl compound or an activated acyl compound is provided. According to this method, a corresponding free amine and its substituted derivative can be produced easily and industrially advantageously from the 2- or 4-nitrobenzenesulfonamide without using a thiol compound.
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- Process for preparation of optically active n-substituted azetidine-2-carboxylic acids
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The object of the present invention is to produce an optically active N-substituted azetidine-2-carboxylic acid by an efficient, expedient and commercially profitable process. The present invention provides a production method of an optically active N-sub
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- Process for cyclizing optically active 4-amino-2-halogenobutyric acids
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The invention provides a process for producing optically active azetidine-2-carboxylic acid with good efficiency, expedience, and commercial advantage, which comprises cyclizing an optically active 4-amino-2-halogenobutyric acid in an optical yield of as high as 90% or more. It is a process for producing optically active azetidine-2-carboxylic acid of the general formula (2), in which * denotes an asymmetric carbon atom, which comprises cyclizing an optically active 4-amino-2-halogenobutyric acid of the general formula (1), in which X represents a halogen atom and * denotes an asymmetric carbon atom, in the presence of an oxide of an alkaline earth metal, a hydroxide of an alkaline earth metal excepting barium, or an organic amine.
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- PROCESS FOR PREPARATION OF OPTICALLY ACTIVE N-SUBSTITUTED AZETIDINE-2-CARBOXYLIC ACIDS
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The object of the present invention is to produce an optically active N-substituted azetidine-2-carboxylic acid by an efficient, expedient and commercially profitable process. The present invention provides a production method of an optically active N-sub
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- PROCESS FOR PRODUCING OPTICALLY ACTIVE AZETIDINE-2-CARBOXYLIC ACIDS
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An optically active N-protected azetidine-2-carboxylic acid (5) can be produced by preparing an optically active 4-amino-2-halobutyric acid (3), ???by halogenating an optically active 3-hydroxy-2-pyrrolidinone (1) with inversion of configuration to prepare an optically active 3-halo-2-pyrrolidinone (2) followed by hydrolysis or, ???by halogenating an optically active 4-amino-2-hydroxybutyric acid ester (6) with inversion of configuration to prepare an optically active 4-amino-2-halobutyric acid ester (7) followed by hydrolysis or, ???by halogenating the compound (6) with inversion of configuration to prepare the compound (7), cyclizing the same to prepare the compound (2) followed by hydrolysis,???further cyclizing the compound (3) followed by treating the reaction product with an amino group-protecting agent.The optical purity of the thus-obtained compound (5) can be improved further by recrystallization.
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- Methods for producing N-protected-azetidine-2-carboxylic acids
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There is disclosed a method for producing an essentially enantiomerically pure N-protected-azetidine-2-carboxylic acid of formula (1): which method is characterized by: subjecting a crude enantiomerically excess N-protected-azetidine-2-carboxylic acid comprising said enantiomer represented by formula (1) in excess to the other enantiomer thereof to crystallization in an organic solvent selected from aromatic hydrocarbon, aliphatic ether, aliphatic alcohol, aliphatic ketone, aliphatic nitrile, aliphatic amide, aliphatic sulfoxide, aliphatic ester and a mixed solvent thereof, wherein R is: an optionally substituted alkyl, alicyclic or alicyclicalkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or a dialkylamino group, and absolute configuration of the asterisked asymmetric carbon atom is S or R.
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- Synthesis of chiral non-racemic azetidines by lipase-catalysed acetylations and their transformation into amino alcohols: Precursors of chiral catalysts
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Azetidinic mono-acetate 7, diol 6b and di-acetate 10a were prepared with high e.e. using PPL-catalysed acetylations. The absolute configurations of all new enantioenriched compounds were assigned by chemical correlation with known compounds. Mono-acetate 7 was then transformed into 30, an amino alcohol of noteworthy potential interest since it represents an interesting precursor for chiral catalysts, such as 32.
- Guanti, Giuseppe,Riva, Renata
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p. 605 - 618
(2007/10/03)
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- Processes for producing azetidine-2-carboxylic acid and intermediates thereof
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PCT No. PCT/JP98/01895 Sec. 371 Date Dec. 30, 1999 Sec. 102(e) Date Dec. 30, 1999 PCT Filed Apr. 24, 1998 PCT Pub. No. WO98/47867 PCT Pub. Date Oct. 29, 1998The present invention has its object to provide a process for producing azetidine-2-carboxylic acid and an intermediate thereof, which is efficient and economical and suited for industrial practice. The present invention is related to a process for producing azetidine-2-carboxylic acid of the following formula (5), which comprises subjecting a 4-oxo-2-azetidinecarboxylic acid derivative represented by the general formula (1) to hydride reduction to give azetidine-2-methanol of the following formula (2), treating the same with an amino-protecting agent to give N-protected azetidine-2-methanol represented by the following general formula (3), treating this with an oxidizing agent to give N-protected azetidine-2-carboxylic acid represented by the following general formula (4) and, further, subjecting the amino-protecting group thereof to elimination.
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- Synthesis and nicotinic acetylcholine receptor in vivo binding properties of 2-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine: A new positron emission tomography ligand for nicotinic receptors
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The lead compound of a new series of 3-pyridyl ethers, the azetidine derivative A-85380 (3[(S)-2-azetidinylmethoxy]pyridine), is a potent and selective ligand for the human α4β2 nicotinic acetylcholine receptor (nAChR) subtype. In vitro, the fluoro derivative of A-85380 (2-fluoro-3[(S)- 2-azetidinylmethoxy]pyridine or F-A-85380) competitively displaced [3H]cytisine or [3H]epibatidine with K(i) values of 48 and 46 pM, respectively. F-A-85380 has been labeled with the positron emitter fluorine- 18(t( 1/2 ) (half-life) = 110 min) by no-carrier-added nucleophilic aromatic substitution by K[18F]F-K222 complex with (3-[2(S)-N-(tert- butoxycarbonyl)-2-azetidinylmethoxy]pyridin-2-yl)trimethylammonium trifluoromethanesulfonate as a highly efficient labeling precursor, followed by TFA removal of the Boc protective group. The total synthesis time was 50- 53 min from the end of cyclotron fluorine-18 production (EOB). Radiochemical yields, with respect to initial [18F]fluoride ion radioactivity, were 68- 72% (decay-corrected) and 49-52% (non-decay-corrected), and the specific radioactivities at EOB were 4-7 Ci/μmol (148-259 GBq/μmol). In vivo characterization of [18F]F-A-85380 showed promising properties for PET imaging of central nAChRs. This compound does not bind in vivo to α7 nicotinic or 5HT3 receptors. Moreover, its cerebral uptake can be modulated by the synaptic concentration of the endogenous ligand acetylcholine. The preliminary PET experiments in baboons with [18F]F-A-85380 show an accumulation of the radiotracer in the brain within 60 min. In the thalamus, a nAChR-rich area, uptake of radioactivity reached a maximum at 60 min (4% I.D./100 mL of tissue). [18F]F-A-85380 appears to be a suitable radioligand for brain imaging nAChRs with PET.
- Dollé, Frédéric,Dolci, Lilian,Valette, Héric,Hinnen, Fran?oise,Vaufrey, Fran?oise,Guenther, Ilonka,Fuseau, Chantal,Coulon, Christine,Bottlaender, Michel,Crouzel, Christian
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p. 2251 - 2259
(2007/10/03)
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- 3-pyridyloxymethyl heterocyclic ether compounds useful in controlling neurotransmitter release
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Novel heterocyclic ether compounds of the formula: STR1 wherein n, *, R1, R2, R3 and y are specifically defined, or pharmaceutically acceptable salts or prodrugs thereof, which are useful in selectively controlling neurotransmitter release; therapeutically-effective pharmaceutical compositions of these compounds; and use of said compositions to selectively control neurotransmitter release in mammals.
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- Synthesis of 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine, a highly potent radioligand for in vivo imaging central nicotinic acetylcholine receptors
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This paper reports the synthesis of 2-fluoro-3-[2(S)-2- azetidinylmethoxy]pyridine and its radiolabeling with fluorine-18 ([18F]FK- K222) by nucleophilic aromatic nitro-to-fluoro substitution in DMSO by conventional heating at 150°C for 20 min or by microwave activation at 100 Watt for 1 min. This fluoro compound is a closely related analog of the high affinity nicotinic ligand A-85380 (3-[2(S)-2-azetidinylmethoxy]pyridine). This compound is the lead compound of a novel 3-pyridyl ether series of new nAChR ligands recently published, and possesses not only subnanomolar comparable to that of epibatidine, for the α4β2 subtype, but also a weaker affinity for the other subtypes or nAChRs. 110-140 mCl (4.1-5.2 GBq) of pure 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine ([18F]fluoro-A-85380) could be obtained in less than 2 hours, with specific radioactivities of 3-5 Ci/μmol (111-185 GBq/μmol) calculated for End of Bombardment (or 1.5-2.5 Ci/μmol (55.5-92.5 GBq/μmol) at End of Synthesis) for a 20 μA, 30 min (36000 μC) irradiation of a 95% enriched [18O]water target with a 16 MeV proton beam [18O(p,n)18F]. Yield (with respect to [18F]fluoride ion) : decay-corrected 49-64% ; non-decay corrected 25-33%. Total synthesis time from EOB : 105-110 min (this includes the recovery of the [18F]fluoride ion from the target and the [18F]FK-K222-complex preparation). Preliminary results in rats showed a substantial uptake of the ligand in the thalamus (1% I.D./g tissue at 30 min) while the cerebellar uptake was 2-fold lower. Thalamic uptake was reduced by 75-85% following a pre treatment with nicotine, cytisine, epibatidine or fluoro-A-85380. The full pharmacological profile and the potential for eventual clinical applications of this ligand as a tracer for PET experiments are currently under investigation.
- Dolle, Frederic,Valette, Heric,Bottlaender, Michel,Hinnen, Francoise,Vaufrey, Francoise,Guenther, Ilonka,Crouzel, Christian
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p. 451 - 463
(2007/10/03)
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- Novel 3-pyridyl ethers with subnanomolar affinity for central neuronal nicotinic acetylcholine receptors
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Recent evidence indicating the therapeutic potential of cholinergic channel modulators for the treatment of central nervous system (CNS) disorders as well as the diversity of brain neuronal nicotinic acetylcholine receptors (nAChRs) have suggested an opportunity to develop subtype-selective nAChR ligands for the treatment of specific CNS disorders with reduced side effect liabilities. We report a novel series of 3-pyridyl ether compounds which possess subnanomolar affinity for brain nAChRs and differentially activate subtypes of neuronal nAChRs. The synthesis and structure-activity relationships for the leading members of the series are described, including A-85380 (4a), which possesses ca. 50 pM affinity for rat brain [3H]-(- )cytisine binding sites and 163% efficacy compared to nicotine to stimulate ion flux at human α4β2 nAChR subtype, and A-84543 (2a), which exhibits 84- fold selectivity to stimulate ion flux at human α4β2 nAChR subtype compared to human ganglionic type nAChRs. Computational studies indicate that a reasonable superposition of a low energy conformer of 4a with (S)-nicotine and (-)-epibatidine can be achieved.
- Abreo, Melwyn A.,Lin, Nan-Horng,Garvey, David S.,Gunn, David E.,Hettinger, Ann-Marie,Wasicak, James T.,Pavlik, Patricia A.,Martin, Yvonne C.,Donnelly-Roberts, Diana L.,Anderson, David J.,Sullivan, James P.,Williams, Michael,Arneric, Stephen P.,Holladay, Mark W.
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p. 817 - 825
(2007/10/03)
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- Studies of Neurokinin Antagonists. 4. Synthesis and Structure-Activity Relationships of Novel Dipeptide Substance P Antagonists: N2--L-prolyl>-N-methyl-N-(phenylmethyl)-3-(2-naphthyl)-L-alaninamide and Its Related Compounds
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As an extension of our studies on discovering a novel substance P (SP) antagonist, we modified the previously reported dipeptide, N2-2-(1H-indol-3-ylcarbonyl)-L-lysyl>-N-methyl-N-(phenylmethyl)-L-phenylalaninamide (2b).The lysine part in 2b was first optimized to a (2S,4R)-hydroxyproline derivative (3h), which is 2-fold more potent than 2b in SP binding assay using guinea pig lung membranes.Next we modified the 1H-indol-3-ylcarbonyl part in 3h.Introduction of a methyl group at the indole nitrogen enhanced the oral activity, while retaining the binding activity.Finally, we modified the phenylalanine part to culminate in the most potent compound 7k (FK888), which is a potent SP antagonist with NK1 selectivity as well as oral activity.
- Hagiwara, Daijiro,Miyake, Hiroshi,Igari, Norihiro,Karino, Masako,Maeda, Yasue,et al.
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p. 2090 - 2099
(2007/10/02)
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- Benzazepine and benzothiazepine derivatives
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Vasodilating activity is exhibited by compounds having the formula STR1 wherein X can be --S--or --CH2 --; and R2 is STR2 depending upon the definition of X.
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- A NEW SYNTHESIS OF OPTICALLY ACTIVE 2-METHOXYCARBONYL-4-AZETIDINONE FROM L-AZETIDINE-2-CARBOXYLIC ACID: UTILITY OF RUTHENIUM TETROXIDE OXIDATION
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A first transformation of L-azetidine-2-carboxylic acid (1) into optically active monocyclic N-unsubstituted β-lactam, (2S)-2-methoxycarbonyl-4-azetidinone (6), has been developed via ruthenium tetroxide (RuO4) oxidation process.
- Tanaka, Ken-ichi,Yoshifuji, Shigeyuki,Nitta, Yoshihiro
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p. 2539 - 2543
(2007/10/02)
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- Synthesis of Pro-Leu-Gly-NH2 Analogues Modified at the Prolyl Residue and Evaluation of Their Effects on the Receptor Binding Activity of the Central Dopamine Receptor Agonist, ADTN
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Several analogues of L-prolyl-L-leucylglycinamide (PLG) were synthesized wherein the prolyl residue was replaced with other heterocyclic amino acid residues.Among the analogues synthesized were D-Pro-Leu-Gly-NH2 (2), 3,4-Pro-Leu-Gly-NH2 (7), and D-Δ3,4-Pro-Leu-Gly-NH2 (8).These analogues were tested for their ability to enhance the binding of the agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene to central dopamine receptors.Analogues 2,3, and 5-7 showed activity comparable to that of PLG, while the tripeptides 4 and 8 were found to be inactive.The results show that the N-terminal prolyl residue of PLG is not essential requirement for this tripeptide's ability to modulate dopamine receptors.
- Johnson, Rodney L.,Rajakumar, G.,Yu, Kuo-Long,Mishra, Ram K.
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p. 2104 - 2107
(2007/10/02)
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