4265-99-0Relevant articles and documents
Structure-Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D
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
, p. 481 - 515 (2021/02/05)
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.
Synthesis of Medium-Ring-Sized Benzolactams by Using Strong Electrophiles and Quantitative Evaluation of Ring-Size Dependency of the Cyclization Reaction Rate
Kurouchi, Hiroaki,Ohwada, Tomohiko
, p. 876 - 901 (2019/12/30)
Benzolactams with medium-sized rings were synthesized via the electrophilic aromatic substitution reaction of carbamoyl cations (R1R2N+═C═O) in good to high yields without dilution. These reactions were utilized to quantitatively examine the extent of retardation of medium-sized ring formation, compared to five- or six-membered ring formation. The order of reaction rates of formation of cyclic benzolactams is six- > five- > seven- > eight- > nine-membered ring at 25 °C. The present reaction provides a route to eight- A nd nine-membered benzolactams.
INHIBITORS OF N-ACYLPHOSPHATIDYLETHANOLAMINE PHOSPHOLIPASE D (NAPE-PLD)
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, (2019/12/15)
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.
Synthesis, structure-activity relationships and molecular modeling studies of new indole inhibitors of monoamine oxidases A and B
La Regina, Giuseppe,Silvestri, Romano,Gatti, Valerio,Lavecchia, Antonio,Novellino, Ettore,Befani, Olivia,Turini, Paola,Agostinelli, Enzo
experimental part, p. 9729 - 9740 (2009/04/06)
New monoamine oxidase inhibitors were synthesized as indole analogues of a previously reported pyrrole series. Several compounds were potent MAO-A (12, 17, 19-22, 31, 36, and 37) or MAO-B (14, 20, 24, 38, 44, and 46) inhibitors, and had Ki values in the nanomolar concentration range. In particular, 22 (Ki = 0.00092 μM, and SI = 68,478) was exceptionally potent and selective as MAO-A inhibitor. In molecular modeling studies, compounds 22, 24, 44, and 46 positioned the indole ring into an aromatic cavity of MAO-A, and established π-π stacking interactions with Tyr407, Tyr444, and FAD cofactor. However, only compound 22 was able to form hydrogen bonds with FAD, a finding which was in accordance with its potent anti-MAO-A activity. Conversely, 22/MAOB complex was highly unstable during the MD simulation.
Beta lactam compounds and their use as inhibitors of tryptase
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Page column 282, (2010/11/29)
Compounds of the formulas: are disclosed. These compounds inhibit tryptase as well as other enzyme systems or are selective tryptase inhibitors and are useful as antiinflammatory agents particularly in the treatment of chronic asthma.
Transformation of Monoamine Oxidase-B Primary Amine Substrates into Time-Dependent Inhibitors. Tertiary Amine Homologues of Primary AMine Substrates
Ding, Charles Z.,Lu, Xingliang,Nishimura, Kuniko,Silverman, Richard B.
, p. 1711 - 1715 (2007/10/02)
A family of N-methylated and N,N-dimethylated alkyl and arylalkylamines was prepared and more than half of the analogues were shown to be time-dependent pseudo-first-order inhibitors of monoamine oxidase-B.Some of the time-dependent inactivators were reversible and others were irreversible with respect to prolonged dialysis following inactivation.Partition ratios ranged from zero to 11 000.These results are rationalized in terms of a combination of an inductive effect and a stereoelectronic effect as a result of hindered rotation of an active site covalent adduct.A molecualr mechanics calculation indicates that there is at least 10 kcal/mol of torsional energy to be overcome in order for the enzyme adduct to be released.These findings show that tertiary amine homologues of primary amine substrates of monoamino oxidase are time-dependent inhibitors, and this should be useful in the design of new inactivators of this enzyme.
Highly Selective Aromatic Chlorination. Part 3. Kinetics and Mechanism of Chlorination of Electron-rich Aromatic Compounds by N-Chloroamines in Acidic Solution
Smith, John R. Lindsay,McKeer, Linda C.,Taylor, Jonathan M.
, p. 1529 - 1536 (2007/10/02)
The highly selective chlorination of electron-rich aromatic compounds with N-chloroamines in trifluoroacetic acid (TFA) is first order in both the aromatic substrate and the chlorinating agent.Kinetic and competitive kinetic studies show that electron-donating substituents on the substrate and electron-withdrawing substituents on the N-chloroamine have a marked rate-enhancing effect.Two mechanisms that fit the experimentally observed kinetics and that account for the high selectivity for 4-chlorination in terms of an electronic effect are proposed, namely an arenium-ion mechanism and an electron-transfer chain reaction.Evidence from chemical trapping experiments and from other studies suggest that for the majority of the substrates the chlorination proceeds by the arenium ion mechanism.However, for substrates, such as 1,4-dimethoxybenzene, that are very susceptible to one-electron oxidation chlorination may proceed at least in part by the electron-transfer chain reaction.
