Design and Optimization of Novel Competitive, Non-peptidic, SARS-CoV-2 Mpro Inhibitors.

The SARS-CoV-2 main protease (Mpro) has been proven to be a highly effective target for therapeutic intervention, yet only one drug currently holds FDA approval status for this target. We were inspired by a series of publications emanating from the Jorgensen and Anderson groups describing the design of potent, non-peptidic, competitive SARS-CoV-2 Mpro inhibitors, and we saw an opportunity to make several design modifications to improve the overall pharmacokinetic profile of these compounds without losing potency. To this end, we created a focused virtual library using reaction-based enumeration tools in the Schrödinger suite. These compounds were docked into the Mpro active site and subsequently prioritized for synthesis based upon relative binding affinity values calculated by FEP+. Fourteen compounds were selected, synthesized, and evaluated both biochemically and in cell culture. Several of the synthesized compounds proved to be potent, competitive Mpro inhibitors with improved metabolic stability profiles.

Neurotherapeutic Potential of Water-Soluble pH-Responsive Prodrugs of EIDD-036 in Traumatic Brain Injury.

The C-20 oxime of progesterone, EIDD-036 (2), demonstrates neuroprotection and improved outcomes in animal models of traumatic brain injury (TBI). However, 2 suffers from poor solubility, which renders it unsuitable for rapid administration. Previous prodrugs of 2 aimed at improving solubility by incorporating enzymatically labile amino acid and phosphate ester promoieties. These approaches were effective but led to limitations with in vivo administration. Herein, we disclose a pH-responsive water-soluble prodrug strategy to improve exposure to 2 through enzyme-independent activation. Compound 13l was identified as a lead that exhibits water-solubility, stability in acidic solutions, and rapid conversion to 2 at physiological pH. Administration of 13l to rats resulted in a twofold increase in exposure to 2 compared to the previous generation phosphate prodrug, EIDD-1723 (6). In a rat model of TBI, treatment with 13l resulted in a significant decrease in cerebral edema when administered postinjury.

The Rigidins: Isolation, Bioactivity, and Total Synthesis-Novel Pyrrolo[2,3-d]Pyrimidine Analogues Using Multicomponent Reactions.

Rigidins (2-6) are pyrrolopyrimidine alkaloids isolated from marine tunicates. Since their isolation, refinement of their total syntheses, and biochemical evaluation, interest toward this pyrrolo[2,3-d]pyrimidine scaffold as a medicinal candidate has been triggered. The derivatization of these natural products has led to the discovery of a novel range of 7-deazahypoxanthines, which exhibit extremely potent anticancer activity in human cancer cell lines. A major breakthrough toward the synthesis of rigidin and various rigidin analogues has been the application of multicomponent reactions (MCRs). The rapid assembly of molecular diversity and flexibility displayed by MCRs makes it an attractive strategy for the preparation of rigidin-inspired small molecules. Furthermore, a number of rigidin-like 7-deazaxanthine compounds have been reported in the literature and the popularity of implementing MCRs to construct these 7-deazaxanthines is highlighted here. It is our hope that the synthetic methods described in this chapter will result in the further generation of rigidin-inspired compounds that will move on from being "hits" into "leads" in the medicinal chemistry drug discovery pipeline and potentially into anticancer therapeutics.