- Antineoplastic agents. 599. Total synthesis of dolastatin 16
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The first 23-step total synthesis of the cyclodepsipeptide dolastatin 16 (1) has been achieved. Synthesis of the dolaphenvaline and dolamethylleuine amino acid units using simplified methods improved the overall efficiency. The formation of the 25-membere
- Pettit, George R.,Smith, Thomas H.,Arce, Pablo M.,Flahive, Erik J.,Anderson, Collin R.,Chapuis, Jean-Charles,Xu, Jun-Ping,Groy, Thomas L.,Belcher, Paul E.,Macdonald, Christian B.
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Read Online
- Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties ()
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Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.
- Vachal, Petr,Duffy, Joseph L.,Campeau, Louis-Charles,Amin, Rupesh P.,Mitra, Kaushik,Murphy, Beth Ann,Shao, Pengcheng P.,Sinclair, Peter J.,Ye, Feng,Katipally, Revathi,Lu, Zhijian,Ondeyka, Debra,Chen, Yi-Heng,Zhao, Kake,Sun, Wanying,Tyagarajan, Sriram,Bao, Jianming,Wang, Sheng-Ping,Cote, Josee,Lipardi, Concetta,Metzger, Daniel,Leung, Dennis,Hartmann, Georgy,Wollenberg, Gordon K.,Liu, Jian,Tan, Lushi,Xu, Yingju,Chen, Qinghao,Liu, Guiquan,Blaustein, Robert O.,Johns, Douglas G.
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supporting information
p. 13215 - 13258
(2021/09/02)
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- Intermediate for preparing halichondrin compound and preparation method thereof
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The invention relates to an intermediate for preparing a halichondrin compound and a preparation method thereof. The invention particularly relates to an intermediate for preparing halichondrin, eribulin or analogues thereof, and a preparation method and application of the intermediate. The intermediate as well as the preparation method and application thereof are used for constructing C20-C26 structural fragments of the halichondrin compound. The initial raw materials of the synthesis route are cheap, easy to obtain, stable in source and reliable in quality; the structural characteristics ofreactants are fully utilized in the selection of a chiral center construction method, so that the synthesis efficiency is practically improved, and the difficulty and risk of product quality control are reduced; and the use of a high-toxicity and expensive organic tin catalyst is avoided, so that the cost and the environmental friendliness are remarkably improved.
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Paragraph 0132-0135
(2020/07/07)
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- SPIRO-SULFONAMIDE DERIVATIVES AS INHIBITORS OF MYELOID CELL LEUKEMIA-1 (MCL-1) PROTEIN
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The disclosure is directed to compounds of Formula I (I) Pharmaceutical compositions comprising compounds of Formula I as well as methods of their use and preparation, are also described.
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Paragraph 00621
(2020/06/01)
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- Nucleophilic halo-michael addition under lewis-base activation
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A simple and general conjugate nucleophilic halogenation is presented. The THTO/halosilane combination has shown the ability to act as a nucleophilic halide source in the conjugate addition to a variety of Michael acceptors. In addition, a straightforward diastereoselective halogen installation using α,β-unsaturated acyloxazolidinones as platforms has been developed.
- Laina-Martín, Víctor,Pérez, Ignacio,Fernández-Salas, Jose A.,Alemán, José
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supporting information
p. 12936 - 12939
(2019/11/05)
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- Visible light photocatalytic asymmetric synthesis of pyrrolo[1,2-: A] indoles via intermolecular [3+2] cycloaddition
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The intermolecular diastereoselective and enantioselective synthesis of pyrrolo[1,2-a]indoles is developed through a [3+2] cycloaddition between silyl-indole derivatives and α,β-unsaturated N-acyl oxazolidinones by merging photocatalysis and Lewis acid catalysis.
- Casado-Sánchez, Antonio,Domingo-Legarda, Pablo,Cabrera, Silvia,Alemán, José
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supporting information
p. 11303 - 11306
(2019/09/30)
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- Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists
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G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.
- Shi, Jun,Gu, Zhengxiang,Jurica, Elizabeth Anne,Wu, Ximao,Haque, Lauren E.,Williams, Kristin N.,Hernandez, Andres S.,Hong, Zhenqiu,Gao, Qi,Dabros, Marta,Davulcu, Akin H.,Mathur, Arvind,Rampulla, Richard A.,Gupta, Arun Kumar,Jayaram, Ramya,Apedo, Atsu,Moore, Douglas B.,Liu, Heng,Kunselman, Lori K.,Brady, Edward J.,Wilkes, Jason J.,Zinker, Bradley A.,Cai, Hong,Shu, Yue-Zhong,Sun, Qin,Dierks, Elizabeth A.,Foster, Kimberly A.,Xu, Carrie,Wang, Tao,Panemangalore, Reshma,Cvijic, Mary Ellen,Xie, Chunshan,Cao, Gary G.,Zhou, Min,Krupinski, John,Whaley, Jean M.,Robl, Jeffrey A.,Ewing, William R.,Ellsworth, Bruce Alan
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p. 681 - 694
(2018/02/16)
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- Palladium-Catalyzed Diastereoselective Synthesis of 3-Arylbutanoic Acid Derivatives
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The first palladium-catalyzed diastereoselective conjugate addition of arylboronic acids to chiral imides is reported. The catalytic system employing 4-tert-butyloxazolidin-2-one as the chiral auxiliary in a mixed solvent system of MeOH/H2O (1:3) under an air atmosphere provides the optically active 3-arylbutanoic acid derivatives in excellent yields with high diastereoselectivity.
- Zhi, Wubin,Li, Jingya,Zou, Dapeng,Wu, Yusheng,Wu, Yangjie
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p. 12286 - 12293
(2017/12/08)
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- Dihydropyrazole GPR40 modulators
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The present invention provides compounds of Formula (I): or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are GPR40 G protein-coupled receptor modulators which may be used as medicaments.
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Page/Page column 47
(2015/10/05)
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- IMIDAZOTRIAZINONE COMPOUNDS
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The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9 and pharmaceutically acceptable salt thereof. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including humans.
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Paragraph 0791; 0792
(2013/10/08)
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- FUSED BICYCLIC OXAZOLIDINONE CETP INHIBITOR
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Compounds having the structure of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis.
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Paragraph 0189; 0190
(2013/05/09)
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- IMIDAZOTRIAZINONE COMPOUNDS
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The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including CNS or neurodegeneration disorder.
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Page/Page column 103
(2012/04/10)
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- Oxazolidine-2-thiones and thiazolidine-2-thiones as nucleophiles in intermolecular michael additions
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Conjugate addition of thiazolidinethiones and oxazolidinethiones to N-crotonylthiazolidinethiones and -oxazolidinethiones was observed in the presence of excess triethylamine in dichloromethane. The addition takes place by the nitrogen of the heterocycle
- Munive, Laura,Rivas, Veronica M.,Ortiz, Aurelio,Olivo, Horacio F.
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supporting information; experimental part
p. 3514 - 3517
(2012/08/08)
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- Doubly diastereoselective conjugate addition of enantiopure lithium amides to enantiopure N-enoyl oxazolidin-2-ones: A mechanistic probe
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The doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a range of enantiopure N-enoyl oxazolidin-2-ones has been used as a mechanistic probe to determine that the reactive conformation is the anti-s-cis form. The β-amino carbonyl products resulting from these conjugate addition reactions are useful templates for further elaboration into an α,β,α-pseudotripeptide.
- Davies, Stephen G.,Fletcher, Ai M.,Hermann, Gesine J.,Poce, Giovanna,Roberts, Paul M.,Smith, Andrew D.,Sweet, Miles J.,Thomson, James E.
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experimental part
p. 1635 - 1648
(2010/10/18)
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- The efficient synthesis of (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid, a chiral β-amino acid with potent affinity for the α2δ protein
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A chiral β-amino acid containing three contiguous chiral centers was synthesized efficiently in 11 steps, employing enantio-enriched β-ketoester as a key intermediate, via stereoselective catalytic hydrogenation of the corresponding enamide. Stereoselecti
- Zhang, Ji,Blazecka, Peter G.,Pflum, Derek A.,Bozelak, Joseph,Vrieze, Derek,Colbry, Norman L.,Hoge, Garrett,Boyles, David C.,Samas, Brian,Curran, Timothy T.,Osuma, Augustine T.,Johnson, Paul,Kesten, Suzanne,Schwarz, Jacob B.,Goodman, Annise,Plummer, Mark,Akin, Anne,Huang, Yun,Lovdahl, Michael,Thorpe, Andrew J.
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scheme or table
p. 1167 - 1170
(2009/06/28)
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- Large-scale synthesis of SB-462795, a cathepsin K inhibitor: the RCM-based approaches
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Two stereoselective syntheses of SB-462795, a highly potent cathepsin K inhibitor, are described. Both routes feature a C5-C6 disconnection by ring closing metathesis to construct an azepane ring and are amenable to large-scale manufacturing.
- Wang, Huan,Matsuhashi, Hayao,Doan, Brian D.,Goodman, Steven N.,Ouyang, Xi,Clark Jr., William M.
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experimental part
p. 6291 - 6303
(2009/12/04)
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- Highly diastereoselective conjugate additions of monoorganocopper reagents to chiral imides
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Stereoselective conjugate additions to chiral N-enoyl amides employing various monoorganocuprate reagents, Li[RCuI], are described. The presence of TMSI in the addition of Li[RCuI] in THF provided the highest stereoselectivities. Reversed major diastereom
- Dambacher, Jesse,Anness, Robert,Pollock, Patrick,Bergdahl, Mikael
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p. 2097 - 2110
(2007/10/03)
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- 2-OXAZOLIDINONES AND THEIR USE AS INHIBITORS OF ANIMAL CELL MOTILITY AND GROWTH
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Cell motility and growth inhibitors, including compounds of the general structural formula (I), and use of the cell motility and cell growth inhibitors, and pharmaceutically acceptable salts, pro-drugs, and solvates thereof, as therapeutic agents, are disclosed.
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- Electrogenerated base-induced N-acylation of chiral oxazolidin-2-ones. 2
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An improved and efficient electrochemical N-acylation of chiral oxazolidin-2-ones has been achieved. The generation of the nitrogen anion is obtained under mild conditions and without addition of base or probase, by direct electrolysis of a solution of Me
- Feroci, Marta,Inesi, Achille,Palombi, Laura,Sotgiu, Giovanni
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p. 1719 - 1721
(2007/10/03)
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- Stereoselective total synthesis of topographically constrained designer amino acids: 2',6'-dimethyl-β-methyltyrosines
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The constrained aromatic α-amino acid 2',6'-dimethyl-β-methyl tyrosine (Figure 1) was designed to provide specific local constraints to peptides or peptide mimetics. We report here methods for the total asymmetric synthesis of all four stereoisomers. The
- Qian,Russell,Boteju,Hruby
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p. 1033 - 1054
(2007/10/02)
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- Efficient Method for the Total Asymmetric Synthesis of the Isomers of β-Methyltyrosine
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α-Amino acids modified at the β-carbon atom can provide topographical constraints when incorporated into a peptide.Such modifications can modulate the physical, chemical, and biological properties of the compound.In order to properly evaluate the effect o
- Nicolas, Ernesto,Russell, K. C.,Knollenberg, J.,Hruby, Victor J.
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p. 7565 - 7571
(2007/10/02)
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