The morphology of the mature motor neuron dendritic arbor is determined by activity-dependent processes occurring during a critical period in early postnatal life. The abundance of the AMPA receptor subunit GluR1 in motor neurons is very high during this period and subsequently falls to a negligible level. To test the role of GluR1 in dendrite morphogenesis, we reintroduced GluR1 into rat motor neurons at the end of the critical period and quantitatively studied the effects on dendrite architecture. Two versions of GluR1 were studied that differed by the amino acid in the "Q/R" editing site. The amino acid occupying this site determines single-channel conductance, ionic permeability, and other essential electrophysiologic properties of the resulting receptor channels. We found large-scale remodeling of dendritic architectures in a manner depending on the amino acid occupying the Q/R editing site. Alterations in the distribution of dendritic arbor were not prevented by blocking NMDA receptors. These observations suggest that the expression of GluR1 in motor neurons modulates a component of the molecular substrate of activity-dependent dendrite morphogenesis. The control of these events relies on subunit-specific properties of AMPA receptors.
A practical synthesis of a key pharmaceutical intermediate, 2-[(1H-pyrrolo[2,3-b]pyridine-4-yl)methylamino]-5-fluoronicotinic acid (1), is described. To introduce the aminomethyl moiety of 2 via a palladium-catalyzed cyanation/reduction sequence, a regioselective chlorination of 7-azaindole via the N-oxide was developed. A highly selective monodechlorination of 2,6-dichloro-5-fluoronicotinic acid was discovered to afford the nicotinic acid 3. The two building blocks 2 and 3 were then coupled to complete the preparation of 1.
A commercial process to manufacture sotorasib (AMG 510),
a first-in-class
KRASG12C inhibitor, is described. Development efforts focused
on rendering a fit-for-purpose early-phase route into a viable long-term
commercial process through the reduction of side reactions to improve
yield and product quality, as well as reducing cycle times of crystallization
processes by improving particle properties and filtration times. These
improvements were key to ensuring clinical supply and commercial launch.
The final route consists of five synthetic operations from starting
material
M-1, including a telescoped
two-step sequence, and a final form-setting crystallization.
The development of a synthetic route to manufacture the drug candidate AMG 925 on kilogram scale is reported herein. The hydrochloride salt of AMG 925 was prepared in 23% overall yield over eight steps from commercially available raw materials, and more than 8 kg of the target molecule were delivered. The synthetic route features a Buchwald−Hartwig amination using BrettPhos as ligand and conducted to afford 12 kg of product in a single batch. In addition, this work highlights the challenges associated with the use of poorly soluble process intermediates in the manufacture of active pharmaceutical ingredients. Creative solutions had to be devised to conduct seemingly routine activities such as salt removal, pH adjustment, and heavy metal scavenging due to the low solubility of the process intermediates. Finally, a slurry-to-slurry amidation protocol was optimized to allow for successful scale-up.
The development of a factory process to manufacture the novel cardiac myosin activator omecamtiv mecarbil (1) is described. Omecamtiv mecarbil is prepared via the convergent synthesis and coupling of two key fragments, aniline 2 and carbamate 4-HCl, which serves as a masked isocyanate. To enable practical access to aniline 2, reduction of the corresponding nitroaromatic was designed to control potential mutagenic impurities. Key to the efficient preparation of 2 was the benzylic bromination of 8 followed by selective debromination of a gem-dibromide byproduct and subsequent alkylation with 5phosphate. Overall, the longest linear sequence consists of six steps, including a final salt formation step to afford the drug substance in 55% overall yield. Because of poor performance of the original free-base form of the drug substance in modifiedrelease formulations, an improved dihydrochloride hydrate form was developed to aid drug product performance and manufacturability.
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