Discovery of First Branched-Chain Ketoacid Dehydrogenase Kinase (BDK) Inhibitor Clinical Candidate PF-07328948.

Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From a starting point with potential idiosyncratic toxicity risk, modification to a benzothiophene core and discovery of a cryptic pocket allowed for improved potency with 3-aryl substitution to arrive at PF-07328948, which was largely devoid of protein covalent binding liability. This BDK inhibitor was shown also to be a BDK degrader in cells and in vivo rodent studies.

High-Throughput Capillary Liquid Chromatography Using a Droplet Injection and Application to Reaction Screening.

The cycle time of a standard liquid chromatography (LC) system is the sum of the time for the chromatographic run and the autosampler injection sequence. Although LC separation times in the 1-10 s range have been demonstrated, injection sequences are commonly >15 s, limiting throughput possible with LC separations. Further, such separations are performed on relatively large bore columns requiring flow rates of ≥5 mL/min, thus generating large volumes of mobile phase waste when used for large scale screening and increasing the difficulty in interfacing to mass spectrometry.

A systematic integrative review examining the impact of Australian rural and remote maternity unit closures.

Background: Rural and remote Australian women are less able to access locally situated maternity care and birthing facilities, largely due to the gradual closures of rural and remote birthing services. Closures have occurred due to workforce issues, safety and quality issues and economic rationalisation of services to offset rising health system costs. An examination of the published literature to gain a deeper understanding of this phenomenon is warranted.

Late-Stage Lead Diversification Coupled with Quantitative Nuclear Magnetic Resonance Spectroscopy to Identify New Structure-Activity Relationship Vectors at Nanomole-Scale Synthesis: Application to Loratadine, a Human Histamine H Receptor Inverse Agonist.

An experimental approach is described for late-stage lead diversification of frontrunner drug candidates using nanomole-scale amounts of lead compounds for structure-activity relationship development. The process utilizes C-H bond activation methods to explore chemical space by transforming candidates into newly functionalized leads. A key to success is the utilization of microcryoprobe nuclear magnetic resonance (NMR) spectroscopy, which permits the use of low amounts of lead compounds (1-5 μmol).

A Modular Approach to the Synthesis of gem-Disubstituted Cyclopropanes.

A diastereoselective, Pd-catalyzed Suzuki-Miyaura coupling reaction of geminal bis(boryl)cyclopropanes has been developed. The reaction offers a highly modular approach to the synthesis of tertiary cyclopropylboronic esters. The resulting boronic esters may be further functionalized to afford a range of gem-disubstituted cyclopropanes, which represent an important structural motif in the pharmaceutical industry.

Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity.

Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds.

Automated solvent system screening for the preparative countercurrent chromatography of pharmaceutical discovery compounds.

A fully automated countercurrent chromatography system has been constructed to rapidly screen the commonly used heptane/ethyl acetate/methanol/water solvent system series and translate the results to preparative scale separations. The system utilizes "on-demand" preparation of the heptane/ethyl acetate/methanol/water solvent system upper and lower phases. Elution-extrusion countercurrent chromatography was combined with non-dynamic equilibrium injection reducing the screening time for each heptane/ethyl acetate/methanol/water system to 17 min.

Biaryl-bridged macrocyclic peptides: conformational constraint via carbogenic fusion of natural amino acid side chains.

A general method for constraining peptide conformations via linkage of aromatic sidechains has been developed. Macrocyclization of suitably functionalized tri-, tetra- and pentapeptides via Suzuki-Miyaura cross-coupling has been used to generate side chain to side chain, biaryl-bridged 14- to 21-membered macrocyclic peptides. Biaryl bridges possessing three different configurations, meta-meta, meta-ortho, and ortho-meta, were systematically explored through regiochemical variation of the aryl halide and aryl boronate coupling partners, allowing fine-tuning of the resultant macrocycle conformation.

Inhibitions of cotton seedling growth by volatile ketones emitted by cover crop residues.

Low-input, sustainable agriculture (LISA) systems can include soil incorporation of residues of weeds and legume cover crop species. However, both seed germination and seedling growth of crops, including cotton (Gossypium hirsutum L.), are inhibited by volatile organic compounds emitted by these residues during decomposition.

Relationships between chemical structure and inhibitory activity of C6 through C 9 volatiles emitted by plant residues.

Leaf, stem, flower, fruit, and root residues of a wide variety of plants have been reported to emit bioactiven-alkanes, 2-alkanols,n-alkanals, 2-alkenals, 2-alkanones, andn-alkanoic acids containing from six to nine carbon atoms. During a 72-hr exposure to the vapor phase of these compounds (6.9, 20.

Volatile seed germination inhibitors from plant residues.

Volatile emissions from residues of the winter cover legumes, Berseem clover (Trifolium alexandrinum L.), hairy vetch [Vicia hirsuta (L.) S.

Inhibition and promotion of germination by several sesquiterpenes.

The sesquiterpene lactones, burrodin, confertiflorin. desacetyl-confertiflorin, dihydroparthenolide, parthenin, and 7α-hydroxy-3-desoxyzaluzanin C, and the sesquiterpene ester guayulin A were assayed at concentrations of 1, 10, and 100 μM for effects on seed germination of 16 dicot and nine monocot species. Six of the dicot and two of the monocot species were affected by one or more of these compounds.

Seed-germination inhibition by volatile alcohols and other compounds associated withAmaranthus palmeri residues.

Effects of 3-pentanone and eight low molecular weight aliphatic alcohols and aldehydes identifed in the mixtures of volatiles released byAmaranthus palmeri S. Wats. (AMAPA) residues were determined on germination of onion, carrot, AMAPA, and tomato seeds.

Volatile methyl ketone seed-germination inhibitors fromAmaranthus palmeri S. Wats. Residues.

The effects of nine methyl ketones previously identified in the mixture of volatiles released byAmaranthus palmeri (AMAPA) residues upon onion, carrot, AMAPA, and tomato seed germination were determined. Three-day exposures to these volatiles significantly inhibited germination of all assay seeds, and the degree of inhibition was dependent upon seed species, exposure time, and concentration. Based on the degree of inhibition observed in both time- and concentration-dependent assays, the following activity series was obtained: 2-octanone, 2-nonanone > 2-undecanone > 2-heptanone > 2-hexanone, 3-methyl-2-butanone, 2-pentanone, 3-hydroxy-2-butanone > 2-butanone.

Identification of volatile allelochemicals fromAmaranthus palmeri S. Wats.

Allelopathic volatiles associated with the weed Palmer amaranth (Amaranthus palmeri S. Wats.; AMAPA) were trapped on Tenax GC, thermally desorbed, and identified by gas chromatography-mass spectroscopy.

Allelochemicals from palmer amaranth,Amaranthus palmeri S. Wats.

The presence of Palmer amaranth (AMAPA) residues in the soil reduced fresh weight accumulation in onions and carrots and markedly decreased seedling field establishment of carrots. Solid-phase separation techniques were used to isolate fractions containing water-soluble organic compounds from AMAPA residues and soil amended with such residues. At concentrations of 20-100 mg/liter most of the organic solids thus extracted were inactive in seed germination assays using onion, carrot, AMAPA, and tomato seeds.