Water-Soluble Progesterone Analogues Are Effective, Injectable Treatments in Animal Models of Traumatic Brain Injury

After more than 30 years of research and 30 failed clinical trials with as many different treatments, progesterone is the first agent to demonstrate robust clinical efficacy as a treatment for traumatic brain injuries. It is currently being investigated in two, independent phase III clinical trials in hospital settings; however, it presents a formidable solubility challenge that has so far prevented the identification of a formulation that would be suitable for emergency field response use or battlefield situations. Accordingly, we have designed and tested a novel series of water-soluble analogues that address this critical need. We report here the synthesis of C-20 oxime conjugates of progesterone as therapeutic agents for traumatic brain injuries with comparable efficacy in animal models of traumatic brain injury and improved solubility and pharmacokinetic profiles. Pharmacodynamic analysis reveals that a nonprogesterone steroidal analogue may be primarily responsible for the observed activity

Discovery of a Fluorinated Enigmol Analog with Enhanced <i>in Vivo</i> Pharmacokinetic and Anti-Tumor Properties

The orally bioavailable 1-deoxy-sphingosine analog, Enigmol, has demonstrated anticancer activity in numerous <i>in vivo</i> settings. However, as no Enigmol analog with enhanced potency <i>in vitro</i> has been identified, a new strategy to improve efficacy <i>in vivo</i> by increasing tumor uptake was adopted. Herein, synthesis and biological evaluation of two novel fluorinated Enigmol analogs, CF₃-Enigmol and CF₂-Enigmol, are reported. Each analog was equipotent to Enigmol <i>in vitro</i>, but achieved higher plasma and tissue levels than Enigmol <i>in vivo</i>. Although plasma and tissue exposures were anticipated to trend with fluorine content, CF₂-Enigmol absorbed into tissue at strikingly higher concentrations than CF₃-Enigmol. Using mouse xenograft models of prostate cancer, we also show that CF₃-Enigmol underperformed Enigmol-mediated inhibition of tumor growth and elicited systemic toxicity. By contrast, CF₂-Enigmol was not systemically toxic and demonstrated significantly enhanced antitumor activity as compared to Enigmol

Discovery of Tetrahydroisoquinoline-Based CXCR4 Antagonists

A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3–650 nM) in assays involving CXCR4 function, including both inhibition of attachment of X4 HIV-1_IIIB virus in MAGI-CCR5/CXCR4 cells and inhibition of calcium release in Chem-1 cells. Series profiling permitted the identification of TIQ-(<i>R</i>)-stereoisomer <b>15</b> as a potent and selective CXCR4 antagonist lead candidate with a promising in vitro profile. The drug-like properties of <b>15</b> were determined in ADME in vitro studies, revealing low metabolic liability potential. Further in vivo evaluations included pharmacokinetic experiments in rats and mice, where <b>15</b> was shown to have oral bioavailability (<i>F</i> = 63%) and resulted in the mobilization of white blood cells (WBCs) in a dose-dependent manner

Sphingolipid Analogues Inhibit Development of Malaria Parasites

<i>Plasmodium</i>-infected erythrocytes have been shown to employ sphingolipids from both endogenous metabolism as well as existing host pools. Therapeutic agents that limit these supplies have thus emerged as intriguing, mechanistically distinct putative targets for the treatment of malaria infections. In an initial screen of our library of sphingolipid pathway modulators for efficacy against two strains of the predominant human malaria species <i>Plasmodium falciparum</i> and <i>Plasmodium knowlesi</i>, a series of orally available, 1-deoxysphingoid bases were found to possess promising in vitro antimalarial activity. To better understand the structural requirements that are necessary for this observed activity, a second series of modified analogues were prepared and evaluated. Initial pharmacokinetic assessments of key analogues were investigated to evaluate plasma and red blood cell concentrations in vivo