- Discovery and Characterization of (R)-6-Neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894), an Alkyne-Lacking Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator Profiled in both Rat and Nonhuman Primates
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We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp3 character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance.
- Stepan, Antonia F.,Claffey, Michelle M.,Reese, Matthew R.,Balan, Gayatri,Barreiro, Gabriela,Barricklow, Jason,Bohanon, Michael J.,Boscoe, Brian P.,Cappon, Gregg D.,Chenard, Lois K.,Cianfrogna, Julie,Chen, Laigao,Coffman, Karen J.,Drozda, Susan E.,Dunetz, Joshua R.,Ghosh, Somraj,Hou, Xinjun,Houle, Christopher,Karki, Kapil,Lazzaro, John T.,Mancuso, Jessica Y.,Marcek, John M.,Miller, Emily L.,Moen, Mark A.,O'Neil, Steven,Sakurada, Isao,Skaddan, Marc,Parikh, Vinod,Smith, Deborah L.,Trapa, Patrick,Tuttle, Jamison B.,Verhoest, Patrick R.,Walker, Daniel P.,Won, Annie,Wright, Ann S.,Whritenour, Jessica,Zasadny, Kenneth,Zaleska, Margaret M.,Zhang, Lei,Shaffer, Christopher L.
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p. 7764 - 7780
(2017/10/10)
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- Amino alcohol-derived chiral ionic liquids: structural investigations toward chiral recognition
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From tentative beginnings, chiral ionic liquids have emerged into functionalized and tailor-made materials that provide novel input in classical asymmetric synthesis and separations. However, despite this broad application range the prediction of any chiral ionic liquids' performance is difficult. We present a systematic study toward the chiral recognition properties of novel ionic liquids with an amino alcohol sub-structure derived from the chiral pool precursors ephedrine, prolinol, and phenylalaninol. The influence of different ionic head groups and core structures on the diastereomeric interactions between racemic Mosher's acid carboxylate and enantiopure chiral ionic liquids was systematically investigated to provide insight into their recognition properties prior to application of these chiral ionic liquids in various fields.
- Vasiloiu, Maria,Cervenka, Isabella,Gaertner, Peter,Weil, Matthias,Schr?der, Christian,Bica, Katharina
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p. 1069 - 1082
(2015/10/19)
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- Diastereoselective synthesis of novel 5-substituted morpholine-3-phosphonic acids: Further exploitation of N-acyliminium intermediates
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The first diastereoselective total synthesis of 5-substituted morpholine-3-phosphonic acids is reported. The principal feature of the synthesis is the introduction of a dimethyl phosphonate group into 5-substituted morpholin-3-ones. The procedure is based
- Bonilla-Landa, Israel,Viveros-Ceballos, José Luis,Ordó?ez, Mario
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p. 485 - 487
(2014/05/06)
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- Enantioselective Hydrosilylation of Ketones Catalyzed by a Readily Accessible N-Heterocyclic Carbene-Ir Complex at Room Temperature
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A series of functionalized azolium compounds were synthesized from chiral α-amino acid derivatives such as β-amino alcohols. of hydroxy-amide-functionalized azolium salts thus obtained with Ag2O afforded N-heterocyclic carbene-Ag (NHC-Ag) complexes. Subsequent treatment of the resulting silver compound with [IrCl(cod)]2 yielded monodentate IrCl(cod)(NHC), which was stable in air. The NHC-Ir complex facilitated efficient asymmetric hydrosilylation of ketones using (EtO)2MeSiH under ambient conditions. A chiral ligand containing an isobutyl stereodirecting group was found to be the best ligand for the functionalized NHC-Ir complexes that were examined. A linear relationship was found between the catalyst ee and the product ee. The hydroxy functional group on the NHC ligand side-arm not only induced stereocontrol but also enhanced the reaction rate.
- Shinohara, Kanako,Kawabata, Shun,Nakamura, Hanako,Manabe, Yoshiki,Sakaguchi, Satoshi
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p. 5532 - 5539
(2014/10/16)
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- Amine-promoted asymmetric (4+2) annulations for the enantioselective synthesis of tetrahydropyridines: A traceless and recoverable auxiliary strategy
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Gone, without a trace: The in situ reaction of 2-(acetoxymethyl)buta-2,3- dienoate and a secondary amine produces a 2-methylene-3-oxobutanoate equivalent that can be used in asymmetric [4+2] annulations with N-tosylimines to provide tetrahydropyridines in
- Hu, Pengfei,Hu, Jian,Jiao, Jiajun,Tong, Xiaofeng
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supporting information
p. 5319 - 5322
(2013/06/05)
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- Organic base effects in NHC promoted O- to C-carboxyl transfer; Chemoselectivity profiles, mechanistic studies and domino catalysis
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The O- to C-carboxyl transfer of oxazolyl carbonates promoted by triazolinylidenes, generated in situ with NEt3, shows a markedly different rate and chemoselectivity profile to the same reaction promoted by triazolinylidenes generated using KHM
- Campbell, Craig D.,Collett, Christopher J.,Thomson, Jennifer E.,Slawin, Alexandra M. Z.,Smith, Andrew D.
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p. 4205 - 4218
(2011/07/29)
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- Catalytic enantioselective Steglich rearrangements using chiral N-heterocyclic carbenes
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The evaluation of a range of enantiomerically pure NHCs, prepared in situ from imidazolinium or triazolium salt precatalysts, to promote the catalytic enantioselective Steglich rearrangement of oxazolyl carbonates to their C-carboxyazlactones, is reported. Modest levels of enantioselectivity (up to 66% ee) are observed using oxazolidinone derived NHCs.
- Campbell, Craig D.,Concellon, Carmen,Smith, Andrew D.
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p. 797 - 811
(2011/08/06)
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- Highly enantioselective intermolecular stetter reactions of β-aryl acceptors: α-ketoester moiety as handle for activation and synthetic manipulations
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The use of β,γ-unsaturated-α-ketoesters in the intermolecular Stetter reaction furnishes 1,2,5-tricarbonyl compounds in high yield and excellent enantioselectivity. The α,δ-diketoesters generated using this methodology serve as useful synthetic building b
- Sanchez-Larios, Eduardo,Thai, Karen,Bilodeau, Francois,Gravel, Michel
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supporting information; experimental part
p. 4942 - 4945
(2011/11/29)
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- Reversal of stereoselectivity in the Cu-catalyzed conjugate addition reaction of dialkylzinc to cyclic enone in the presence of a chiral azolium compound
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Reversal of enantioselectivity in a Cu-catalyzed asymmetric conjugate addition reaction of dialkylzinc to cyclic enone with use of the same chiral ligand was successfully achieved. The reaction of 2-cyclohexen-1-one (30) with Et2Zn catalyzed by
- Shibata, Naoatsu,Okamoto, Masaki,Yamamoto, Yuko,Sakaguchi, Satoshi
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experimental part
p. 5707 - 5715
(2010/10/21)
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- 4-(1,3-Thiazol-2-yl)morpholine derivatives as inhibitors of phosphoinositide 3-kinase
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4-(1,3-Thiazol-2-yl)morpholine derivatives have been identified as potent and selective inhibitors of phosphoinositide 3-kinase. The SAR data of selected examples are presented and the in vivo profiling of compound 18 is shown to demonstrate the utility of this class of compounds in xenograft models of tumor growth.
- Alexander, Rikki,Balasundaram, Ahrani,Batchelor, Mark,Brookings, Daniel,Crepy, Karen,Crabbe, Tom,Deltent, Marie-France,Driessens, Frank,Gill, Andrew,Harris, Sue,Hutchinson, Gillian,Kulisa, Claire,Merriman, Mark,Mistry, Prakash,Parton, Ted,Turner, James,Whitcombe, Ian,Wright, Sara
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scheme or table
p. 4316 - 4320
(2009/04/06)
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- FUSED THIAZOLE DERIVATIVES AS KINASE INHIBITORS
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A series of 5,6-dihydro-l,3-benzothiazol-7(4H)-one derivatives, and analogues thereof, which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety, being selective inhibitors of PD kinase enzymes, are accordingly of b.enefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.
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Page/Page column 51
(2008/06/13)
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- A synthesis of (S)-3-(phenylmethyl)morpholine from (S)-phenylalanol
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A preparation of (S)-3-(phenylmethyl)morpholine from (S)-phenylated is described.
- Shawe, Thomas T.,Koenig Jr., George J.,Ross, Andrew A.
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p. 1777 - 1782
(2007/10/03)
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- Modified Di- and Tripeptides of the C-Terminal Portion of Oxytocin and Vasopressin as Possible Cognition Activation Agents
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A number of peptides and modified peptides were synthesized and studied for their ability to reverse electroconvulsive shock-induced amnesia in rodents.A few of these peptides were selected for secondary evaluation in tests of short-term memory in rats and aged rhesus monkeys.A number of the peptides and modified peptides were active in the amnesia reversal test.In selected secondary tests, however, the chosen compounds failed to show significant activity in enhancing memory.New methods for preparing methyleneamino and methyleneoxy isosters of peptides are reportrd.Other modified peptides also included methylenethio, methylenesulfonyl, and ethylene isosteres in place of the normal peptide amide bond.
- Nicolaides, E. D.,Tinney, F. J.,Kaltenbronn, J. S.,Repine, J. T.,DeJohn, D. A.,et al.
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p. 959 - 971
(2007/10/02)
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- The Formation of Complexes between Aza Derivatives of Crown Ethers and Primary Alkylammonium Salts. Part 7. Chiral Derivatives of Aza Crown Ethers
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A number of optically active derivatives of diaza-15-crown-5- and diaza-18-crown-6 have been synthesised using amino acids as the source of chirality.The diaza-18-crown-6-derivatives (21) show enantioselectivity in the complexation of 1-phenylethylammoniu
- Chadwick, Derek J.,Cliffe, Ian A.,Sutherland, Ian O.,Newton, Roger F.
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p. 1707 - 1717
(2007/10/02)
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