Reduction of N-Protected Amino Acids to Amino Alcohols and Subsequent Re-Oxidation to Original N-Protected Amino Acids

For the synthesis of certain molecules of interest in Dr. Richard Olsen\u27s laboratory it was necessary to produce N-protected a-amino alcohols from N-protected amino acids and subsequently, after further synthesis steps, to oxidize the hydroxyl functionalities of these molecules back to carboxylic acids. A number of methods are known for the reduction of carboxylic acids to alcohols; several methods are also reported in the chemical literature for the oxidation of alcohols to carboxylic acids. The problem in finding a suitable general method, is that the amino acid side chains affect the re activity and chemistry differently in each specific case. I report a method that has been shown to be effective for the reduction and subsequent re-oxidation of a number of N-carbobenzoxy and N-tert-butyloxycarbonyl protected amino acids

The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy.

During studies to extend the half-life of crystalline nanoformulated antiretroviral therapy (nanoART) the mixed lineage kinase-3 inhibitor URMC-099, developed as an adjunctive neuroprotective agent was shown to facilitate antiviral responses. Long-acting ritonavir-boosted atazanavir (nanoATV/r) nanoformulations co-administered with URMC-099 reduced viral load and the numbers of HIV-1 infected CD4+ T-cells in lymphoid tissues more than either drug alone in infected humanized NOD/SCID/IL2Rγc-/- mice. The drug effects were associated with sustained ART depots. Proteomics analyses demonstrated that the antiretroviral responses were linked to affected phagolysosomal storage pathways leading to sequestration of nanoATV/r in Rab-associated recycling and late endosomes; sites associated with viral maturation. URMC-099 administered with nanoATV induced a dose-dependent reduction in HIV-1p24 and reverse transcriptase activity. This drug combination offers a unique chemical marriage for cell-based viral clearance. From the Clinical Editor: Although successful in combating HIV-1 infection, the next improvement in antiretroviral therapy (nanoART) would be to devise long acting therapy, such as intra-cellular depots. In this report, the authors described the use of nanoformulated antiretroviral therapy given together with the mixed lineage kinase-3 inhibitor URMC-099, and showed that this combination not only prolonged drug half-life, but also had better efficacy. The findings are hoped to be translated into the clinical setting in the future

Discovery, Synthesis, and Characterization of an Orally Bioavailable, Brain Penetrant Inhibitor of Mixed Lineage Kinase 3

Inhibition of mixed lineage kinase 3 (MLK3) is a potential strategy for treatment of Parkinson’s disease and HIV-1 associated neurocognitive disorders (HAND), requiring an inhibitor that can achieve significant brain concentration levels. We report here URMC-099 (<b>1</b>) an orally bioavailable (<i>F</i> = 41%), potent (IC₅₀ = 14 nM) MLK3 inhibitor with excellent brain exposure in mouse PK models and minimal interference with key human CYP450 enzymes or hERG channels. The compound inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat-injected brains of mice. Compound <b>1</b> likely functions in HAND preclinical models by inhibiting multiple kinase pathways, including MLK3 and LRRK2 (IC₅₀ = 11 nM). We compare the kinase specificity and BBB penetration of <b>1</b> with CEP-1347 (<b>2</b>). Compound <b>1</b> is well tolerated, with excellent in vivo activity in HAND models, and is under investigation for further development