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Research has been conducted on the naphthalene building blocks. The alternate route developed for the synthesis of these building blocks is described.

The first total synthesis of ancistrocladidine 7,3'-linked naphthylisoquninoline alkaloid is completed, with the key feature of the synthesis being the formation of the extremely hindered biaryl linkage by ortho-arylation of a naphthol with an aryllead triacetate. Initial efforts were focused on the generation of a heteroaryl lead species, which would have allowed a convergent synthesis to be developed.

The isomerization-Claisen rearrangement (ICR) reactions of boron-substituted di(allyl) ethers, the properties of the derived beta-boryl aldehydes, and the utility of these species as conduits to Claisen adducts previously inaccessible from the ICR methodology are described. The merging of ICR methodology with ensuing Suzuki cross-coupling reactions will expand the utility of the ICR technology in various synthesis activities.

A study aimed at the broad exploitation of claisen-derived alpha-chiral aldehydes in synthesis activities, and developed highly stereoselective Claisen rearrangements from easily prepared di(allyl) ethers. The claisen rearrangements involved catalyzed olefin isomerization to generate the vinyl ether moiety followed by thermal sigmatropic rearrangement to afford syn-2,3-dialkyl-4-pentenal derivatives with high diastereoselectivity.

Abstract: Voltage-gated sodium (Nav) channels present untapped therapeutic value for better and safer pain medications. The Nav1.8 channel isoform is of particular interest because of its location on peripheral pain fibers and demonstrated role in rodent preclinical pain and neurophysiological assays. To-date, no inhibitors of this channel have been approved as drugs for treating painful conditions in human, possibly because of challenges in developing a sufficiently selective drug-like molecule with necessary potency not only in human but also across preclinical species critical to the preclinical development path of drug discovery. In addition, the relevance of rodent pain assays to the human condition is under increasing scrutiny as a number of mechanisms (or at the very least molecules) that are active in rodents have not translated to humans, and direct impact on pain fibers has not been confirmed in vivo. In this report, we have leveraged numerous physiological end points in nonhuman primates to evaluate the analgesic and pharmacodynamic activity of a novel, potent, and selective Nav1.8 inhibitor compound, MSD199. These pharmacodynamic biomarkers provide important confirmation of the in vivo impact of Nav1.8 inhibition on peripheral pain fibers in primates and have high translational potential to the clinical setting. These findings may thus greatly improve success of translational drug discovery efforts toward better and safer pain medications, as well as the understanding of primate biology of Nav1.8 inhibition broadly., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

The Mycobacterium abscessus drug development pipeline is poorly populated, with particularly few validated target-lead couples to initiate de novo drug discovery. Trimethoprim, an inhibitor of dihydrofolate reductase (DHFR) used for the treatment of a range of bacterial infections, is not active against M. abscessus . Thus, evidence that M. abscessus DHFR is vulnerable to pharmacological intervention with a small molecule inhibitor is lacking. Here, we show that the pyrrolo-quinazoline PQD-1, previously identified as a DHFR inhibitor active against Mycobacterium tuberculosis , exerts whole cell activity against M. abscessus . Enzyme inhibition studies showed that PQD-1, in contrast to trimethoprim, is a potent inhibitor of M. abscessus DHFR and over-expression of DHFR causes resistance to PQD-1, providing biochemical and genetic evidence that DHFR is a vulnerable target and mediates PQD-1's growth inhibitory activity in M. abscessus . As observed in M. tuberculosis , PQD-1 resistant mutations mapped to the folate pathway enzyme thymidylate synthase (TYMS) ThyA. Like trimethoprim in other bacteria, PQD-1 synergizes with the dihydropteroate synthase (DHPS) inhibitor sulfamethoxazole (SMX), offering an opportunity to exploit the successful dual inhibition of the folate pathway and develop similarly potent combinations against M. abscessus . PQD-1 is active against subspecies of M. abscessus and a panel of clinical isolates, providing epidemiological validation of the target-lead couple. Leveraging a series of PQD-1 analogs, we have demonstrated a dynamic structure-activity relationship (SAR). Collectively, the results identify M. abscessus DHFR as an attractive target and PQD-1 as a chemical starting point for the discovery of novel drugs and drug combinations that target the folate pathway in M. abscessus ., Competing Interests: C.J.B., A.E.M., E.B.N., D.B.O., and R.W. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Modification of potent, selective metabotropic glutamate receptor 2 negative allosteric modulator (mGluR 2 NAM) led to a series of analogues with excellent binding affinity, lipophilicity, and suitable physicochemical properties for a PET tracer with convenient chemical handles for incorporation of a 11 C or 18 F radiolabel. [ 11 C]MK-8056 was synthesized and evaluated in vivo and demonstrated appropriate affinity, selectivity, and physicochemical properties to be used as a positron emission tomography tracer for mGluR 2 ., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Chemo- and stereoselective Ir(I)-catalyzed isomerization of 1,1-disubstituted and trisubstituted allylic ethers and in situ [3,3] sigmatropic rearrangement of the resulting allyl vinyl ethers provide for the highly stereoselective construction of quaternary carbon stereocenters. The olefin isomerization-Claisen rearrangement (ICR) sequence allows adjacent quaternary-tertiary stereocenter relationships to be established with excellent diastereoselection. Several complementary strategies for enantioselective quaternary carbon synthesis derive directly from the ICR reaction design.