45eb8cb47d8fa5c4582765d0d3b9b0b9 molecules-30-02078-v2.pdf 3260334d1aade793b2d637eaf4317ddc364a0f9d molecules-30-02078-v2.pdf 14332c7b7b5ffbe7ccda848919f7145740a9088dddd102f08fe39a3dc0343234 molecules-30-02078-v2.pdf Title: Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates Subject: Imidazoline I2 receptors (I2-IR) are untapped therapeutic targets lacking a structural description. Although the levels of I2-IR are dysregulated in a plethora of illnesses, the arsenal of ligands that can modulate I2-IR is limited. In this framework, we have reported several new structural families embodying the iminophosphonate functional group that have an excellent affinity and selectivity for I2-IR, and selected members have demonstrated relevant pharmacological properties in murine models of neurodegeneration and Alzheimer’s disease. Starting with these iminophosphonates, we continued to exploit their high degree of functionalization through a short and efficient synthesis to access unprecedented 2,3-di, 2,2,3-tri, 2,3,4-tri, and 2,2,3,4-tetrasubstituted diethyl (pyrrolidine-2-yl) phosphonates. The stereochemistry of the new compounds was unequivocally characterized by X-ray crystallographic analyses. Two selected compounds with structural features shared with the starting products were pharmacologically evaluated, allowing us to deduce the required key structural motifs for biologically active aminophosphonate derivatives. Keywords: -aminophosphonate; pyrroline; phosphonic ester; (pyrrolidine-2-yl)phosphonate; phosphoproline; imidazoline I2 receptor ligand Author: Andrea Bagán, Alba López-Ruiz, Sònia Abás, Elies Molins, Belén Pérez, Itziar Muneta-Arrate, Luis F. Callado and Carmen Escolano Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Thu May 8 06:03:00 2025 CEST ModDate: Thu May 8 07:28:24 2025 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2439608 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- MGAGVG+EURM10 Type 1 Builtin yes yes yes 10 0 WLFTRW+VnURWPalladioL-Bold Type 1 Custom yes yes yes 15 0 ILXGXV+VnURWPalladioL Type 1 Custom yes yes yes 21 0 ZKKUGL+URWPalladioL-Roma Type 1 Custom yes yes yes 26 0 IWKJPV+URWPalladioL-Bold Type 1 Custom yes yes yes 32 0 HJOTSY+URWPalladioL-Ital Type 1 Custom yes yes yes 37 0 BWDROB+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 66 0 FSCKST+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 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2023-05-18) Date: 2025-06-04 02:09:51 CEST RepresentationInformation: molecules-30-02078-v2.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-06-03 09:10:10 CEST Size: 2439608 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 610 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results and Discussion Destination: section.2 Item: Title: Materials and Methods Destination: section.3 Children: Item: Title: Chemistry Destination: subsection.3.1 Children: Item: Title: General Information Destination: subsubsection.3.1.1 Item: Title: General Procedure for the Reduction of 1a and 1b Destination: subsubsection.3.1.2 Item: Title: General Procedure for the Reduction of 1c, 1d, 1e, 1f and 1g Destination: subsubsection.3.1.3 Item: Title: General Procedure for the Treatment with Resin and Hydrogenation of 3a, 3b, 3c, 3d, and 3e Destination: subsubsection.3.1.4 Item: Title: Reductive Amination Reaction Destination: subsubsection.3.1.5 Item: Title: X-Ray Crystallographic Analysis of PIPred02, CPP06 Destination: subsection.3.2 Item: Title: Binding Studies Destination: subsection.3.3 Children: Item: Title: Preparation of Cellular Membranes Destination: subsubsection.3.3.1 Item: Title: Competition Binding Assays Destination: subsubsection.3.3.2 Item: Title: Conclusions Destination: section.4 Item: Title: References Destination: appendix.A. Info: Title: Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates Author: Andrea Bagán, Alba López-Ruiz, Sònia Abás, Elies Molins, Belén Pérez, Itziar Muneta-Arrate, Luis F. Callado and Carmen Escolano Subject: Imidazoline I2 receptors (I2-IR) are untapped therapeutic targets lacking a structural description. Although the levels of I2-IR are dysregulated in a plethora of illnesses, the arsenal of ligands that can modulate I2-IR is limited. In this framework, we have reported several new structural families embodying the iminophosphonate functional group that have an excellent affinity and selectivity for I2-IR, and selected members have demonstrated relevant pharmacological properties in murine models of neurodegeneration and Alzheimer’s disease. Starting with these iminophosphonates, we continued to exploit their high degree of functionalization through a short and efficient synthesis to access unprecedented 2,3-di, 2,2,3-tri, 2,3,4-tri, and 2,2,3,4-tetrasubstituted diethyl (pyrrolidine-2-yl) phosphonates. The stereochemistry of the new compounds was unequivocally characterized by X-ray crystallographic analyses. Two selected compounds with structural features shared with the starting products were pharmacologically evaluated, allowing us to deduce the required key structural motifs for biologically active aminophosphonate derivatives. 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