eprintid: 37337 rev_number: 31 userid: 3575 dir: disk0/00/03/73/37 datestamp: 2019-09-26 21:32:36 lastmod: 2020-09-26 05:15:51 status_changed: 2019-09-26 21:32:36 type: thesis_degree metadata_visibility: show contact_email: ecarder240@gmail.com eprint_status: archive creators_name: Carder, Evan creators_email: ejc26@pitt.edu creators_id: ejc26 title: Synthetic Efforts Toward P97 AAA+ ATPase and P75 Neurotrophin Receptor Inhibitors ispublished: unpub divisions: sch_as_chemistry full_text_status: public keywords: P97 AAA+ ATPase, P75 Neurotrophin Receptor, Medicinal Chemistry, Inhibitors abstract: The first chapter presented in this dissertation describes the synthesis of diverse 3-sulfanyl-1,2,4-triazole allosteric p97 AAA+ ATPase inhibitors for structure activity/property relationship (SAR/SPR) investigations. This work supported an iterative medicinal chemistry strategy that led to the systematic development of allosteric p97 inhibitors that demonstrated single-digit nanomolar biochemical potency. We were able to scale-up selected analogues to the gram-scale. Further, we synthesized inhibitors to covalently modify p97, as well as potential p97 protein degraders that utilize the hydrophobic tag (HyT) strategy. The second chapter describes a gram-scale synthesis of known p75 neurotrophin receptor inhibitors LM11A-31 and LM11A-24 without the requirement for chromatography. Subsequent investigation of LM11A-31 key pharmacophore features was evaluated through a molecular docking study and the synthesis of LM11A-31 derivatives for SAR investigations. The pursuit of novel p75NTR inhibitors led to the synthesis of the LM11A-31 and LM11A-24 hybrid analog series as well as the 5-aminooxazole series. The chapter is concluded with efforts toward the 5-aminooxazole series, leading to the development of novel methodology that enabled C-5 regioselective direct amination followed by C-2 direct (het)arylation of 4-cyanooxazole. date: 2019-09-26 date_type: published pages: 546 institution: University of Pittsburgh refereed: TRUE etdcommittee_type: committee_chair etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_name: Wipf, Peter etdcommittee_name: Koide, Kazunori etdcommittee_name: Islam, Kabirul etdcommittee_name: Gold, Barry etdcommittee_email: pwipf@pitt.edu etdcommittee_email: koide@pitt.edu etdcommittee_email: kai27@pitt.edu etdcommittee_email: goldbi@pitt.edu etdcommittee_id: pwipf etdcommittee_id: Koide etdcommittee_id: Kai27 etdcommittee_id: goldbi etd_defense_date: 2019-07-26 etd_approval_date: 2019-09-26 etd_submission_date: 2019-08-08 etd_release_date: 2019-09-26 etd_access_restriction: 1_year etd_patent_pending: TRUE thesis_type: dissertation degree: PhD citation: Carder, Evan (2019) Synthetic Efforts Toward P97 AAA+ ATPase and P75 Neurotrophin Receptor Inhibitors. Doctoral Dissertation, University of Pittsburgh. (Unpublished) document_url: http://d-scholarship-dev.library.pitt.edu/37337/1/Evan%20Carder_PhD%20Dissertation_Final_1.pdf