Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.
As
practitioners of organic chemistry strive to deliver efficient
syntheses of the most complex natural products and drug candidates,
further innovations in synthetic strategies are required to facilitate
their efficient construction. These aspirational breakthroughs often
go hand-in-hand with considerable reductions in cost and environmental
impact. Enzyme-catalyzed reactions have become an impressive and necessary
tool that offers benefits such as increased selectivity and waste
limitation. These benefits are amplified when enzymatic processes
are conducted in a cascade in combination with novel bond-forming
strategies. In this article, we report a highly diastereoselective
synthesis of MK-1454, a potent agonist of the stimulator of interferon
gene (STING) signaling pathway. The synthesis begins with the asymmetric
construction of two fluoride-bearing deoxynucleotides. The routes
were designed for maximum convergency and selectivity, relying on
the same benign electrophilic fluorinating reagent. From these complex
subunits, four enzymes are used to construct the two bridging thiophosphates
in a highly selective, high yielding cascade process. Critical to
the success of this reaction was a thorough understanding of the role
transition metals play in bond formation.
Novel ZnX 2 -modulated Pd/C and Pt/C catalysts were developed to chemoselectively hydrogenate halogen-substituted nitroarenes, alkenes, benzyl ethers, and aromatic ketones.
Herein
is described the development of a large-scale manufacturing
process for molnupiravir, an orally dosed antiviral that was recently
demonstrated to be efficacious for the treatment of patients with
COVID-19. The yield, robustness, and efficiency of each of the five
steps were improved, ultimately culminating in a 1.6-fold improvement
in overall yield and a dramatic increase in the overall throughput
compared to the baseline process.
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