23580-89-4Relevant 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.
PRODUCTION OF AMINES VIA A HYDROAMINOMETHYLATION REACTION USING IMINIUM REACTANTS
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Page/Page column 33-34, (2020/05/14)
Provided is a process for producing an amine via a hydroaminomethylation reaction of a non- aromatic C-C double bond, said process comprising a step of reacting a compound comprising a non-aromatic C-C double bond with an iminium ion in a solvent comprising an alcohol, wherein the iminium ion is represented by the following formula (I): wherein R1 and R2 are independently hydrogen or selected from the group consisting of an aliphatic hydrocarbon group which may be substituted, an aromatic hydrocarbon group which may be substituted, an aliphatic heterocyclic group which may be substituted, an aromatic heterocyclic group which may be substituted and of combinations thereof, such as an aralkyl group which may be substituted; and R1 and R2 may be bonded to each other to form a ring together with the nitrogen atom to which they are bound; and wherein R1 and R2 are not both hydrogen and at least one of R1 and R2 carries a hydrogen atom at a carbon atom in ex? position to the nitrogen atom of the iminium ion.
A General Acid-Mediated Hydroaminomethylation of Unactivated Alkenes and Alkynes
Kaiser, Daniel,Tona, Veronica,Gon?alves, Carlos R.,Shaaban, Saad,Oppedisano, Alberto,Maulide, Nuno
supporting information, p. 14639 - 14643 (2019/09/17)
In comparison to the extensively studied metal-catalyzed hydroamination reaction, hydroaminomethylation has received significantly less attention despite its considerable potential to streamline amine synthesis. State-of-the-art protocols for hydroaminomethylation of alkenes rely largely on transition-metal catalysis, enabling this transformation only under highly designed and controlled conditions. Here we report a broadly applicable, acid-mediated approach to the hydroaminomethylation of unactivated alkenes and alkynes. This methodology employs cheap, readily available, and bench-stable reactants and affords the desired amines with excellent functional group tolerance and impeccable regioselectivity. The broad scope of this transformation, as well as mechanistic investigations and in situ domino functionalization reactions are reported.
