Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors

The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailability in rats and monkeys. Compound 30 (Sch-417690/Sch-D), a potent inhibitor of HIV-1 entry into target cells, is currently in clinical trials.

Aurora kinases are cell cycle regulated serine/threonine kinases that have been linked to cancer. Compound 1 was identified as a potent Aurora inhibitor but lacked oral bioavailability. Optimization of 1 led to the discovery of a series of fluoroamine and deuterated analogues, exemplified by compound 25, with an improved pharmacokinetic profile. We found that blocking oxidative metabolism at the benzylic position and decreasing the basicity of the amine are important to obtaining compounds with good biological profiles and oral bioavailability.

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We report on the preparation and the physical properties of superconducting (TaNb) 1− (ZrHfTi) high-entropy alloy films. The films were prepared by means of magnetron sputtering at room temperature, with ranging from 0 to 1 with an average thickness of 600 -950 nm. All films crystallize in a pseudo body-centered cubic (BCC) structure. For samples with < 0.65, the normal-state properties are metallic, while for ≥ 0.65 the films are weakly insulating. The transition from metallic to weakly insulating occurs right at the near-equimolar stoichiometry. We find all films, except for = 0 or 1, to become superconducting at low temperatures, and we interpret their superconducting properties within the Bardeen-Cooper-Schrieffer (BCS) framework. The highest transition temperature Tc = 6.9 K of the solid solution is observed for ~0.43. The highest upper-critical field Bc2(0) = 11.05 T is found for the near-equimolar ratio ~0.65, where the mixing entropy is the largest. The superconducting parameters derived for all the films from transport measurements are found to be close to those that are reported for amorphous superconductors. Our results indicate that these films of high-entropy alloys are promising candidates for superconducting device fabrication.

The imidazo-[1,2-a]-pyrazine (1) is a dual inhibitor of Aurora kinases A and B with modest cell potency (IC 50 = 250 nM) and low solubility (5 μM). Lead optimization guided by the binding mode led to the acyclic amino alcohol 12k (SCH 1473759), which is a picomolar inhibitor of Aurora kinases (TdF K d Aur A = 0.02 nM and Aur B = 0.03 nM) with improved cell potency (phos-HH3 inhibition IC 50 = 25 nM) and intrinsic aqueous solubility (11.4 mM). It also demonstrated efficacy and target engagement in human tumor xenograft mouse models.

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