The observed structure-activity relationship of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compounds with a good balance of selectivity, cellular potency, and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies. When dosed orally, the optimized compound reduced blood pressure in mice overexpressing human WNK1, and induced diuresis, natriuresis and kaliuresis in spontaneously hypertensive rats (SHR), confirming that this mechanism of inhibition of WNK kinase activity is effective at regulating cardiovascular homeostasis.

Protein kinases are known for their highly conserved adenosine triphosphate (ATP)-binding site, rendering the discovery of selective inhibitors a major challenge. In theory, allosteric inhibitors can achieve high selectivity by targeting less conserved regions of the kinases, often with an added benefit of retaining efficacy under high physiological ATP concentration. Although often overlooked in favor of ATP-site directed approaches, performing a screen at high ATP concentration or stringent hit triaging with high ATP concentration offers conceptually simple methods of identifying inhibitors that bind outside the ATP pocket. Here, we applied the latter approach to the With-No-Lysine (K) (WNK) kinases to discover lead molecules for a next-generation antihypertensive that requires a stringent safety profile. This strategy yielded several ATP noncompetitive WNK1-4 kinase inhibitors, the optimization of which enabled cocrystallization with WNK1, revealing an allosteric binding mode consistent with the observed exquisite specificity for WNK1-4 kinases. The optimized compound inhibited rubidium uptake by sodium chloride cotransporter 1 (NKCC1) in HT29 cells, consistent with the reported physiology of WNK kinases in renal electrolyte handling.

The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.

Small molecules that inhibit the metabolic enzyme NAMPT have emerged as potential therapeutics in oncology. As part of our effort in this area, we took a scaffold morphing approach and identified 3-pyridyl azetidine ureas as a potent NAMPT inhibiting motif. We explored the SAR of this series, including 5 and 6 amino pyridines, using a convergent synthetic strategy. This lead optimization campaign yielded multiple compounds with excellent in vitro potency and good ADME properties that culminated in compound 27.

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The microstructure and crystal phase in 2.8 mol! yttria-stabilized zirconia polycrystals were investigated. Starting powders were prepared by wet dispersing and mixing using an agitator mill or by the liquid phase precipitation method. The composites powders were sintered at 1275-1600? C and then analyzed. Solid phase method SPM powders showed higher sinterability than those of the liquid phase precipitation method LPM powders, and high density samples consisting of fine grains could be obtained at lower sintering temperatures than from LPM powders. Unlike the LPM sample, the cubic and tetragonal phase was formed in the SPM sample at low sintering temperature, because there was the region of high and low Y 3 ion concentration in the material. As the sintering temperature increased, the cubic phase decreased and tetragonal phase increased by the progress of the diffusion of Y 3 ions. And then, Y 3 ions segregated at grain boundaries, and tetragonal grains containing cubic phase at grain boundary regions were formed. The thermal expansion curve for the SPM sample samples sintered at 1275? C exhibited a monoclinic to tetragonal transformation during the heating stage; however, the expansion was linear during the cooling stage, as was the case for both SPM samples sintered at higher temperatures and the LPM samples. The thermal expansion behavior of the SPM sample suggested that the monoclinic phase was essentially not present within the sample, although the transformed monoclinic phase in a surface layer by grinding stresses was exist.

Spontaneous trimerization of fluoro(triisopropylsilyl)acetylene, prepared from 1,1‐difluoroethylene in one step, gives the corresponding fluorinated Dewar benzene derivative, whose structure was determined by X‐ray diffraction (see picture).

The palladium catalyzed cross-coupling reactions of aryl iodides and 5-tributylstannyl-4-fluoropyrazole prepared from fluoro(tributylstannyl)acetylene proceeded smoothly giving the corresponding 5-aryl-4-fluoropyrazole in good yields.