- Stereoselective synthesis of (2S,3S,4R,5S)-proline-3,4,5-d3
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A catalytic deuteration of protected 3,4-dehydro-L-proline using RuCl2(PPh3)3 followed by RuO4-oxidation gave a 3,4-dideuterated L-pyroglutamic acid derivative which is considered to be a promising precursor for various deuterated amino acids. The present study demonstrates a stereoselective reduction of the amide carbonyl moiety leading to L-proline derivatives in which all of the ring methylenes are stereoselectively labeled with deuterium.
- Oba, Makoto,Terauchi, Tsutomu,Hashimoto, Jun,Tanaka, Tomohiro,Nishiyama, Kozaburo
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- Diastereoselective functionalization of 5-hydroxy prolinates by tandem Horner-Emmons-Michael reaction
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The tandem Horner-Emmons-Michael reaction of the hemiaminal derived from N-BOC protected pyroglutamic esters with stabilised phosphonates gives 5-substituted prolinates in high diastereomeric and enantiomeric excess through 1,4-asymmetric induction process.
- Collado, Ivan,Ezquerra, Jesus,Vaquero, Juan Jose,Pedregal, Concepcion
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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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- Discovery and Development of 3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane Hydrochloride (SUVN-911): A Novel, Potent, Selective, and Orally Active Neuronal Nicotinic Acetylcholine α4β2 Receptor Antagonist for the Treatment of Depression
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A series of chemical optimizations guided by in vitro affinity at the α4β2 receptor in combination with selectivity against the α3β4 receptor, pharmacokinetic evaluation, and in vivo efficacy in a forced swim test resulted in identification of 3-(6-chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane hydrochloride (9h, SUVN-911) as a clinical candidate. Compound 9h is a potent α4β2 receptor ligand with a Ki value of 1.5 nM. It showed >10 μM binding affinity toward the ganglionic α3β4 receptor apart from showing selectivity over 70 other targets. It is orally bioavailable and showed good brain penetration in rats. Marked antidepressant activity and dose-dependent receptor occupancy in rats support its potential therapeutic utility in the treatment of depression. It does not affect the locomotor activity at doses several folds higher than its efficacy dose. It is devoid of cardiovascular and gastrointestinal side effects. Successful long-term safety studies in animals and phase-1 evaluation in healthy humans for safety, tolerability, and pharmacokinetics paved the way for its further development.
- Nirogi, Ramakrishna,Mohammed, Abdul Rasheed,Shinde, Anil K.,Ravella, Srinivasa Rao,Bogaraju, Narsimha,Subramanian, Ramkumar,Mekala, Venkat Reddy,Palacharla, Raghava Choudary,Muddana, Nageswararao,Thentu, Jagadeesh Babu,Bhyrapuneni, Gopinadh,Abraham, Renny,Jasti, Venkat
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p. 2833 - 2853
(2020/03/05)
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- Synthesis and biological evaluation of all eight stereoisomers of DPP-IV inhibitor saxagliptin
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All eight stereoisomers of saxagliptin have been synthesized and evaluated for their inhibitory activity against DPP-IV. It was unambiguously confirmed that the configuration of saxagliptin was critical to potent inhibition of DPP-IV. Docking study was performed to elucidate the configuration-activity relationship of saxagliptin stereoisomers. Tyr662 and Tyr470 have been suggested as the key residues of DPP-IV interacting with the inhibitors. This work provides valuable information for further inhibitor design against DPP-IV.
- Dong, Jizhe,Gong, Yanchun,Liu, Jun,Chen, Xiangfeng,Wen, Xiaoan,Sun, Hongbin
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p. 1383 - 1393
(2014/03/21)
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- Stereoselective construction of a key hydroindole precursor of epidithiodiketopiperazine (ETP) natural products
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An asymmetric synthetic strategy for constructing the divergent-synthesis monomer of epidithiodiketopiperazine (ETP) natural products has been successfully developed. The functionalized 2,3,3a,4,7,7a-hexahydroindole scaffold was constructed by a diastereoselective inverse electron-demand Diels-Alder (IEDDA) reaction. This journal is the Partner Organisations 2014.
- Feng, Minghao,Jiang, Xuefeng
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p. 9690 - 9692
(2014/08/18)
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- STRUCTURAL MIMETICS OF PROLINE-RICH PEPTIDES AND THE PHARMACEUTICAL USE THEREOF
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The invention relates to compounds of general formula (I), which can be used particularly as structural mimetics of proline-rich peptides and are therefore capable of binding PRM binding domains (proline-rich motif binding domains) of proteins. The invention also relates to the use of said compounds as pharmaceutical active agents and the use of these pharmaceutical active agents for treating bacterial diseases, neurodegenerative diseases and tumours.
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- Synthesis of macrocyclic analogues of the neuroprotective agent glycyl-l-prolyl-l-glutamic acid (GPE)
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The syntheses of seven macrocyclic analogues of the neuroprotective tripeptide glycyl-l-prolyl-l-glutamic acid (GPE) 1 are described. Macrocycles 6 and 7 mimic the cis conformer of GPE whereas macrocycles 2-5, 8, and 9 mimic the trans conformer of GPE. The macrocyclic peptides of well-defined geometry were prepared via Grubbs ring closing metathesis of an appropriate diene precursor. In turn each of the diene precursors were prepared from the readily available allyl-substituted amino acid building blocks 12, 13, 14, 27, 36 and 51. The Royal Society of Chemistry 2006.
- Harris, Paul W. R.,Brimble, Margaret A.
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p. 2696 - 2709
(2008/02/08)
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- Trans-2,5-Disubstituted pyrrolidines: Rapid stereocontrolled access from sulfones
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A direct method for the reliable synthesis of trans-2,5-distributed pyrrolidines from pyroglutamic acid that was conducted at scale and without chromatographic purification of key intermediates was investigated. An analogous reaction involving the partial reduction of succinimides and displacement of the resulting lactol with benzenesulfinic acid yields sulfonyl pyrrolidinones. It was found that a highly diastereoselective and general approach to 2,5-difunctionalized pyrrolidines could be achieved by applying this strategy to the pyroglutamate system. The four step synthesis required no chromatographic purification of intermediates, where the product sulfone was readily purified by recrystallization and the sequence proceeded in 52% overall yield. The results show that such an approach would be of great importance for the preparation of substituted pyrrolidines in natural product systems.
- Moloney, Mark G.,Panchal, Terry,Pike, Richard
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p. 3894 - 3897
(2008/09/18)
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- Rigid dipeptide mimetics. Stereocontrolled synthesis of all eight stereoisomers of 2-oxo-3-(N-Cbz-amino)-1-azabicyclo[4.3.0]nonane-9-carboxylic Acid ester
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Stereopure 2-oxo-3-(N-Cbz-amino)-1-azabicyclo[4.3.0]nonane-9-carboxylic acid (AZABIC) methyl and ethyl esters (14a/b and 23a/b, respectively) have been synthesized from readily available (R)- and (S)-pyroglutamic esters 1 and 15. Altogether all eight possible stereoisomers of this type of compound have been prepared in gram quantities. (C) 2000 Elsevier Science Ltd.
- Mulzer, Johann,Schülzchen, Frank,Bats, Jan-W.
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p. 4289 - 4298
(2007/10/03)
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- Potent bicyclic lactam inhibitors of thrombin: Part I: P3 modifications
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Peptidomimetic inhibitors of general structure 1 have been prepared. Optimization of the binding affinities of these compounds through variation of the P3 hydrophobic residue is described. Selected substituted bicylic lactams displayed interesting pharmacological profiles both in vitro and in vivo.
- St-Denis, Yves,Augelli-Szafran, Corinne E.,Bachand, Benoit,Berryman, Kent A.,DiMaio, John,Doherty, Annette M.,Edmunds, Jeremy J.,Leblond, Lorraine,Levesque, Sophie,Narasimhan, Lakshmi S.,Penvose-Yi, Jan R.,Rubin, J. Ronald,Tarazi, Micheline,Winocour, Peter D.,Siddiqui, M. Arshad
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p. 3193 - 3198
(2007/10/03)
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- Probing the importance of spacial and conformational domains in captopril analogs for angiotensin converting enzyme activity
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A new synthesis of 4,5-methano-L-prolines and the enzymatic activity of the corresponding N-(3-mercapto-2-R-methyl-propionyl) analogs as inhibitors of angiotensin converting enzyme are described.
- Hanessian, Stephen,Reinhold, Ulrich,Saulnier, Michel,Claridge, Stephen
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p. 2123 - 2128
(2007/10/03)
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- A convenient procedure for the conversion of N-Boc protected pyrrolidinone derivatives into their corresponding enecarbamates
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When N-Boc protected pyrrolidinone derivatives are treated by Dibal-H and then by quinolinium camphorsulfonate, they are converted into their corresponding enecarbamate.
- Cossy,Cases,Gomez Pardo
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p. 2769 - 2776
(2007/10/03)
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- C-glycosylation of cyclic N-acyliminium ions with trimethylsilyloxyfuran
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C-glycosylation of 2-methoxy-5-alkoxycarbonyl pyrrolidines with trimethylsilyloxyfuran allows us to obtain the corresponding pyrrolidines contigus to a α,β-unsaturated butyrolactone.
- Pichon, Marianne,Figadere, Bruno,Cave, Andre
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p. 7963 - 7966
(2007/10/03)
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- Stereoselective Addition of Grignard-Derived Organocopper Reagents to N-Acyliminium Ions: Synthesis of Enantiopure 5- and 4,5-Substituted Prolinates
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Alkylation of nonracemic N-acyliminium ions derived from proline and 4-substituted prolines has been extended to different types of Grignard-derived organocopper reagents.The reaction proceeds with high yield and stereoselectivity to yield 5-mono- and 4,5-disubstituted prolinates.The stereochemistry is controlled by the formation of a RCu-? complex intermediate between the N-acyliminium ion, the carbonyl group of the ester, and the copper species.
- Collado, Ivan,Ezquerra, Jesus,Pedregal, Concepcion
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p. 5011 - 5015
(2007/10/03)
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- Highly Chemoselective Reduction of N-Boc Protected Lactams
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N-Boc protected lactams can be reduced chemoselectively in the presence of other groups such as esters, nitriles carbamates or double bonds by first reducing the amide carbonyl group into the corresponding hemiaminal using lithium triethylborohydride foll
- Pedregal, Concepcion,Ezquerra, Jesus,Escribano, Ana,Carreno, M. Carmen,Ruano, Jose L. Garcia
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p. 2053 - 2056
(2007/10/02)
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