- Structure-Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D
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N-Acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is regarded as the main enzyme responsible for the biosynthesis of N-acylethanolamines (NAEs), a family of bioactive lipid mediators. Previously, we reported N-(cyclopropylmethyl)-6-((S)-3-hydroxypyrrolidin-1-yl)-2-((S)-3-phenylpiperidin-1-yl)pyrimidine-4-carboxamide (1, LEI-401) as the first potent and selective NAPE-PLD inhibitor that decreased NAEs in the brains of freely moving mice and modulated emotional behavior [ Mock et al. Nat Chem. Biol., 2020, 16, 667-675 ]. Here, we describe the structure-activity relationship (SAR) of a library of pyrimidine-4-carboxamides as inhibitors of NAPE-PLD that led to the identification of LEI-401. A high-throughput screening hit was modified at three different substituents to optimize its potency and lipophilicity. Conformational restriction of an N-methylphenethylamine group by replacement with an (S)-3-phenylpiperidine increased the inhibitory potency 3-fold. Exchange of a morpholine substituent for an (S)-3-hydroxypyrrolidine reduced the lipophilicity and further increased activity by 10-fold, affording LEI-401 as a nanomolar potent inhibitor with drug-like properties. LEI-401 is a suitable pharmacological tool compound to investigate NAPE-PLD function in vitro and in vivo.
- Mock, Elliot D.,Kotsogianni, Ioli,Driever, Wouter P. F.,Fonseca, Carmen S.,Vooijs, Jelle M.,Den Dulk, Hans,Van Boeckel, Constant A. A.,Van Der Stelt, Mario
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p. 481 - 515
(2021/02/05)
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- Palladium-Catalyzed C(sp2)-H Olefination of Free Primary and Secondary 2-Phenylethylamines: Access to Tetrahydroisoquinolines
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A rapid construction of THIQs by a Pd(II)-catalyzed C(sp2)-H olefination of free primary and secondary 2-phenylethylamines with high step- and atom-economy was reported. Notably, no substituent was required at the α-position to the amino group of the 2-phenylethylamines. The substrate scope was broad, and the reaction could also be applied to generate THIQs from the biologically active molecules such as the drug molecule baclofen and phenylalanine ester.
- Fan, Shuai,Ding, Yongzheng,Chen, Xiaoxi,Gao, Yuzhen,Fu, Lei,Li, Shangda,Li, Gang
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p. 13003 - 13012
(2019/10/11)
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- INHIBITORS OF N-ACYLPHOSPHATIDYLETHANOLAMINE PHOSPHOLIPASE D (NAPE-PLD)
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The invention relates to a compound of the formula (I) as novel inhibitor of N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD), and to use thereof for the prophylaxis or treatment of diseases associated with NAPE-PLD. wherein in a ring A, X1 is N, or CR4; X2 is N or CR5; X3 is N or CH; with the proviso that at least one of X1 and X3 is N.
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- NB 06: From a simple lysosomotropic aSMase inhibitor to tools for elucidating the role of lysosomes in signaling apoptosis and LPS-induced inflammation
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Ceramide generation is involved in signal transduction of cellular stress response, in particular during stress-induced apoptosis in response to stimuli such as minimally modified Low-density lipoproteins, TNFalpha and exogenous C6-ceramide. In this paper we describe 48 diverse synthetic products and evaluate their lysosomotropic and acid sphingomyelinase inhibiting activities in macrophages. A stimuli-induced increase of C16-ceramide in macrophages can be almost completely suppressed by representative compound NB 06 providing an effective protection of macrophages against apoptosis. Compounds like NB 06 thus offer highly interesting fields of application besides prevention of apoptosis of macrophages in atherosclerotic plaques in vessel walls. Most importantly, they can be used for blocking pH-dependent lysosomal processes and enzymes in general as well as for analyzing lysosomal dependent cellular signaling. Modulation of gene expression of several prominent inflammatory messengers IL1B, IL6, IL23A, CCL4 and CCL20 further indicate potentially beneficial effects in the field of (systemic) infections involving bacterial endotoxins like LPS or infections with influenza A virus.
- Blaess, Markus,Bibak, Nelly,Claus, Ralf A.,Kohl, Matthias,Bonaterra, Gabriel A.,Kinscherf, Ralf,Laufer, Stefan,Deigner, Hans-Peter
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supporting information
p. 73 - 104
(2017/10/17)
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- Discovery of Cytochrome P450 4F11 Activated Inhibitors of Stearoyl Coenzyme A Desaturase
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Stearoyl-CoA desaturase (SCD) catalyzes the first step in the conversion of saturated fatty acids to unsaturated fatty acids. Unsaturated fatty acids are required for membrane integrity and for cell proliferation. For these reasons, inhibitors of SCD represent potential treatments for cancer. However, systemically active SCD inhibitors result in skin toxicity, which presents an obstacle to their development. We recently described a series of oxalic acid diamides that are converted into active SCD inhibitors within a subset of cancers by CYP4F11-mediated metabolism. Herein, we describe the optimization of the oxalic acid diamides and related N-acyl ureas and an analysis of the structure-activity relationships related to metabolic activation and SCD inhibition.
- Winterton, Sarah E.,Capota, Emanuela,Wang, Xiaoyu,Chen, Hong,Mallipeddi, Prema L.,Williams, Noelle S.,Posner, Bruce A.,Nijhawan, Deepak,Ready, Joseph M.
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p. 5199 - 5221
(2018/06/13)
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- Reductive N-methylation of amines with calcium hydride and Pd/C catalyst
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The methylation of amines by paraformaldehyde in the presence of calcium hydride as a source of hydrogen and palladium on charcoal as catalyst was studied. Depending on the quantity of paraformaldehyde, monomethylated and dimethylated amines were selectively and efficiently prepared in one pot with good yields.
- Guyon, Carole,Duclos, Marie-Christine,Métay, Estelle,Lemaire, Marc
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p. 3002 - 3005
(2016/07/06)
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- α-Diazo-β-ketonitriles: Uniquely reactive substrates for arene and alkene cyclopropanation
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An investigation of the intramolecular cyclopropanation reactions of α-diazo-β-ketonitriles is reported. These studies reveal that α-diazo-β-ketonitriles exhibit unique reactivity in their ability to undergo arene cyclopropanation reactions; other similar acceptor-acceptor- substituted diazo substrates instead produce mixtures of C-H insertion and dimerization products. α-Diazo-β-ketonitriles also undergo highly efficient intramolecular cyclopropanation of tri- and tetrasubstituted alkenes. In addition, the α-cyano-α-ketocyclopropane products are demonstrated to serve as substrates for SN2, SN2′, and aldehyde cycloaddition reactions.
- Nani, Roger R.,Reisman, Sarah E.
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p. 7304 - 7311
(2013/06/27)
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- Potent and selective adenosine A2A receptor antagonists: 1,2,4-Triazolo[1,5-c]pyrimidines
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Antagonism of the adenosine A2a receptor offers great promise in the treatment of Parkinson's disease. In the course of exploring pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonists, which led to clinical candidate SCH 420814, we prepared 1,2,4-triazolo[1,5-c]pyrimidines with potent and selective (vs A1) A2a antagonist activity, including oral activity in the rat haloperidol-induced catalepsy model. Structure-activity relationships and plasma levels are described for this series.
- Neustadt, Bernard R.,Liu, Hong,Hao, Jinsong,Greenlee, William J.,Stamford, Andrew W.,Foster, Carolyn,Arik, Leyla,Lachowicz, Jean,Zhang, Hongtao,Bertorelli, Rosalia,Fredduzzi, Silva,Varty, Geoffrey,Cohen-Williams, Mary,Ng, Kwokei
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scheme or table
p. 967 - 971
(2009/09/06)
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- Ind2TiMe2-catalyzed addition of methyl- and ethylamine to alkynes
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We describe a very simple hydrogenation-like experimental protocol for the addition of gaseous methyl- and ethylamine to alkynes in the presence of Ind2TiMe2 as the catalyst. For efficient hydroamination reactions it is sufficient to stir a mixture of the alkyne and the catalyst in toluene at temperatures between 80°C (terminal alkynes) and 105°C (internal alkynes) under a constant pressure of 1 atm of the corresponding amine. After subsequent reduction of the initially formed imines, methyl- and ethylamine derivatives are the final products of the described one-pot reaction sequences. In the case of 2-alkyl-1-phenylalkynes as starting materials, biologically interesting 2-phenylethylamine derivatives possessing a small methyl or ethyl substituent at the N atom are easily accessible by the new reaction protocol. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.
- Marcsekova, Klaudia,Wegener, Bernd,Doye, Sven
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p. 4843 - 4851
(2007/10/03)
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- Carbamate linkers as latent N-methylamines in solid phase synthesis
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A new linker strategy for solid phase synthesis has been developed. It utilizes LAH reduction of a carbamate connection to Wang resin which results in N-methylamines, a useful functionality in medicinal chemistry.
- Ho, Chih Y.,Kukla, Michael J.
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p. 2799 - 2802
(2007/10/03)
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- Single electron transfer promoted photocyclization reactions of (aminoalkyl)cyclohexenones. Mechanistic and synthetic features of processes involving the generation and reactions of amine cation and α-amino radicals
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Mechanistic and synthetic aspects of the SET-induced photocyclization reactions of a series of α-, β-, and γ-(aminoethyl)cyclohexenones have been explored. These investigations have provided results that demonstrate that both direct (in MeOH) and SET-sensitized photocyclization reactions of members of this series containing N-(trimethylsilyl)methyl substituents serve as highly efficient methods for preparation of both fused and spiro N-heterobicyclic systems. In addition, as observed earlier, the solvent has been shown to play an important role in governing the chemoselectivity (i.e., amine cation radical desilylation vs deprotonation) of these photocyclizations. Specifically, desilylation is preferred in the polar protic solvent MeOH while deprotonation is favored in the aprotic MeCN. The results also show that the kinetic acidities of amine cation radicals, as judged by photoproduct distributions from reactions conducted in MeCN, are governed in a predictable way by substituents that control the stabilities of the resulting α-amino radical intermediates. Finally, the SET-sensitized reactions of these (aminoethyl)cyclohexenones that proceed via the radical cyclization mechanism are shown to display modest-to-low degrees of stereoselectivity.
- Xu, Wei,Zhang, Xiao-Ming,Mariano, Patrick S.
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p. 8863 - 8878
(2007/10/02)
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