The work presented herein constitutes the effort of one graduate student to mimic the efforts of a small biotech company. To this end, success was had on multiple fronts and the author is excited to showcase the data and results obtained on two different projects. Both projects focus on different targets of potential male contraceptives: spermiogenesis and sperm motility. In chapter one a very brief summary and introduction to the field of contraceptive research is presented, serving as an hors d’oeuvre to the main course of chapters two through four. Chapters two and three detail the efforts towards developing blockers of an intriguing calcium ion channel called CatSper. The proper function of this channel is required for fertilization, as knockout mice are completely infertile with no deleterious phenotypes observed. Inhibitors of this channel are well-suited to applications in non-hormonal male contraception and two approaches towards developing blockers of this channel are described in chapters two and three. Chapter two discusses the work done towards converting the endogenous activator of the channel, progesterone, into a blocker via systematic modifications to the steroid scaffold This approach yielded three compounds able to block the physiologically relevant openers of the channel and revealed discrepancies between steroidal blockers and classic t-type calcium channel blockers. The discovery, efficacy and discrepancies of and between these compounds is discussed at length. Chapter three details the hit-to-lead development of two new scaffolds of CatSper blockers found via an HTS campaign which finished in 2012. Matrix chemistry was utilized to generate libraries of focused compounds. The activity of these compounds in a developed influx assay could lead to further analog generation and eventually two submicromolar blockers of the channel were discovered and characterized. Additionally, the first steps of a fragment-inspired approach towards the development of a second scaffold is described in the latter half of chapter three. Finally, chapter four discusses the efforts of a separate project, focusing on a class of molecules termed iminosugars, specifically aminocyclopentitols. These compounds strongly modulate glycosphingolipid processing, resulting in infertility from improper spermatogenesis. A series of compounds were synthesized and showed potent, and more importantly, selective inhibition of the enzyme responsible for degradation of these lipids (GBA2). Iminosugars, as a whole, are hindered by species-specific efficacy observations and the compounds synthesized and evaluated as part of Chapter 4 could help to illuminate these discrepancies in the future, should the desire arise to explore these observations further.
University of Minnesota Ph.D. dissertation. July 2019. Major: Medicinal Chemistry. Advisor: Gunda Georg. 1 computer file (PDF); xlii, 344 pages.
The Development Of Potential Male Contraceptives Via Inhibition Of Catsper And Also GBA2.
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