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Synthetic Efforts Toward P97 AAA+ ATPase and P75 Neurotrophin Receptor Inhibitors

Carder, Evan (2019) Synthetic Efforts Toward P97 AAA+ ATPase and P75 Neurotrophin Receptor Inhibitors. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Carder, Evanejc26@pitt.eduejc26
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWipf, Peterpwipf@pitt.edupwipf
Committee MemberKoide, Kazunorikoide@pitt.eduKoide
Committee MemberIslam, Kabirulkai27@pitt.eduKai27
Committee MemberGold, Barrygoldbi@pitt.edugoldbi
Date: 26 September 2019
Date Type: Publication
Defense Date: 26 July 2019
Approval Date: 26 September 2019
Submission Date: 8 August 2019
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 546
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: P97 AAA+ ATPase, P75 Neurotrophin Receptor, Medicinal Chemistry, Inhibitors
Date Deposited: 26 Sep 2019 21:32
Last Modified: 26 Sep 2020 05:15


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