عنوان

Synthetic Efforts toward p97 AAA+ ATPaseand p75 Neurotrophin Receptor Inhibitors

TL52642

انگلیسی

Synthetic Efforts toward p97 AAA+ ATPaseand p75 Neurotrophin Receptor Inhibitors

[Thesis]

Carder, Evan J.

Wipf, Peter

University of Pittsburgh

2019

547 p.

Ph.D.

University of Pittsburgh

2019

The first chapter presented in this thesis 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.

Organic chemistry

Carder, Evan J.

Wipf, Peter

University of Pittsburgh

p

[Thesis]

276903

a

Y