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Synthesis and evaluation of halogenated 20-HETE formation inhibitors

Zhan, Yunpeng (2019) Synthesis and evaluation of halogenated 20-HETE formation inhibitors. Master's Thesis, University of Pittsburgh. (Unpublished)

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20-hydroxyecosatetraenoic acid (20-HETE) and epoxyecosatetraenoic acids (EETs) are metabolites of arachidonic acid (AA) formed via CYP hydroxylases and CYP epoxygenases. 20-HETE is a potent vasoconstrictor while EETs show opposite vasodilation activity. A number of studies suggest neuroprotective effects of 20-HETE formation inhibition in animal models of subarachnoid hemorrhage (SAH) and ischemic stroke. These results indicate that 20-HETE formation inhibition is a promising approach for the treatment of brain injury after stroke. Several compounds, such as, 1-ABT, 17-ODYA, 10-SUYS, DDMS and DBDD show 20-HETE formation inhibition. However, their use in treatment has been impeded by shortcomings such as weak potency, low selectivity and poor BBB penetration. 20-HETE formation inhibitors HET0016 and TS-011 exhibit high potency and selectivity but are plagued by poor pharmacokinetic properties. Compound 24 is another 20-HETE formation inhibitor where the labile formamidine moiety seen in HET0016 and TS-011 is replaced with its isostere pyrazole. Unfortunately, compound 24 still suffers from poor metabolic stability. Novel leads UPMP00010 and UPMP00019 were synthesized in the McDermott lab with higher metabolic stability than 24. Their derivatives with simple non-halogen substitutions on the phenyl moiety show improved potency. This work was focused on the synthesis of compounds with halogen substitutions on the UPMP00010/UPMP00019 scaffold with the aim to evaluate their biological activities. 20 compounds with CNS drug likeness characteristics were synthesized. Available data for these compounds shows that compound 16a has very high potency against 20-HETE formation in human and rat microsomal preparations (IC50=49.5 nM in HLM, IC50=337 nM in RLM) and high metabolic stability (100% of original compound remaining after 30 minutes incubation in HLM). Compound 17a also shows high potency and metabolic stability (100% @30 min incubation in HLM) as well as high CNS permeability potential (Papp, A-B=41.8×10-6 cm/s, efflux ratio=0.672). Compounds 20a and 21a are also attractive according to their activities in both human and rat microsomes.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Zhan, Yunpengypzhan@outlook.comYUZ127
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorMcDermott, Leelam179@pitt.edulam179
Committee MemberIyer, Premapci2@pitt.edupci2
Committee MemberFeng, Zhiweizhf11@pitt.eduzhf11
Date: 16 April 2019
Date Type: Publication
Defense Date: 4 April 2019
Approval Date: 16 April 2019
Submission Date: 12 April 2019
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 132
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Design and synthesis of novel 20-HETE formation inhibitors for the treatment of stroke
Date Deposited: 16 Apr 2019 14:32
Last Modified: 16 Apr 2019 14:32


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