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Multikilogram manufacturing process of the Halaven® C14–C35 fragment is described. The synthesis features convergent assembly of subunits by iterative asymmetric Ni/Cr-mediated coupling executed in fixed equipment.

Polymorphism is an interesting property of crystalline substances and is of importance in pharmaceutical development. Studies were conducted to identify the most stable of the five polymorphic (one hydrate and four anhydrous) forms of the active pharmaceutical ingredient (API) E3210. Between the different polymorphs, the transformation mechanisms and thermodynamic stability relationships were complex. Forms A and B were further characterized by differential scanning calorimetry (DSC) at various heating rates and by powder X-ray diffractometry (PXRD; isothermal and temperature-controlled). Analysis by DSC revealed that Form A displayed a single and large endothermic melting peak. Form B displayed two small peaks, one endothermic peak and the other exothermic; the endothermic peak was an enantiotropically related reversible transformation from Form B to Form B′, and the exothermic peak was a monotropically related thermodynamically irreversible transformation from Form B′ to Form A. Thus, Forms B and B′ were enantiotropically related polymorphs, and both were monotropically related to Form A. Form A was the most stable polymorphic form and Form B was metastable.

E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,10-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione)] is a novel anti-inflammatory agent that has potent inhibitory effects on the production of proinflammatory cytokines from leukocytes and antiproliferative activity on keratinocytes. To characterize the in vivo pharmacological activity of E6201, topically administered E6201 was evaluated in several different animal models of dermatitis. E6201 formulated as an ointment or cream showed dose-dependent inhibition of croton oil-induced acute edema formation and neutrophil infiltration into mouse skin. In addition, E6201 cream inhibited the 1-fluoro-2,4-dinitrobenzene-induced contact hypersensitivity reaction mediated by T cells in mice. In this model, E6201 cream also suppressed the migration of neutrophils and lymphocytes into the inflammatory site. Pretreatment with E6201 cream attenuated phorbol-12 myristate 13-acetate-induced ornithine decarboxylase activity, a marker of proliferation in epidermis. Furthermore, E6201 ointment showed inhibitory effects on both mezerein-induced and interleukin (IL)-23-induced epidermal hyperplasia. E6201 also suppressed T cell receptor-stimulated IL-17 production from human T cells. These results indicate that topically administered E6201 may be a useful agent for the prevention and treatment of cutaneous inflammatory and hyperproliferative diseases such as psoriasis.

When lead-acid batteries are used at high temperatures, corrosion is sometimes observed in negative components made of lead-antimony alloys. This corrosion seems to be caused by the antimony contained in lead alloys. We examined the effects of temperature, the concentration of sulfuric acid, and the configuration of test specimens on negative electrode corrosion. We also explored the mechanism by which negative component corrosion occurs when using lead-antimony alloys. Specimens in the electrolyte were not corroded at all, but portions just above electrolyte level and inside tiny spaces were corroded. The reason for this corrosion seems to be as follows. Corroded areas are covered with an electrolyte film that has a high resistance, so they cannot be polarized to the full cathodic protection potential. However, as lead-antimony alloys have a dendritic microstructure, with metallic antimony dispersed throughout the lead phase, local cell reactions between Sb and Pb occur in corroding areas, resulting in the evolution of hydrogen gas and the formation of lead sulfate.

Since increased tissue factor (TF) in human atherosclerotic plaques is believed to trigger thrombotic events, TF/factor VIIa (FVIIa) inhibition might have prophylactic potential for atherothrombosis such as acute coronary syndrome (ACS). Although recent clinical observation by rivaroxaban provides a scientific rationale for the addition of anticoagulant to current antiplatelet treatment, these might have potential to increase bleeding. It is therefore important that emerging anticoagulants demonstrate additive antithrombotic effects with no concomitant increase in bleeding for ACS indication. We recently discovered ER-410660, a potent TF/FVIIa inhibitor. It suppressed venous thrombosis without affecting bleeding time and suggested that ER-410660 could act as a novel anticoagulant with a low bleeding risk. In the photochemically-induced thrombosis (PIT) model, the thrombus after vessel-wall injury has been developed by the deposition of TF, platelets, and fibrin. Therefore, we hypothesized that ER-410660 would be effective in the PIT model and could show enough margin against bleeding. The antithrombotic effects of ER-410660 and acetylsalicylic acid (ASA), both alone and in combination, was assessed using a rat PIT model. We also measured the bleeding time of ER-410660 in combination with ASA using a rat tail-transection model. Intravenous (iv) pretreatment with ER-410660 prolonged the time to occlusion (TTO) of the artery. The TTO was doubled at 0.99 mg/kg (95% CI, 0.51-1.9). Orally administered ASA also showed antithrombotic effect, and the TTO was doubled at approximately 12 mg/kg. Combined administration of 1 mg/kg ER-410660 (iv) and 10 mg/kg ASA (orally) showed an additive antithrombotic effect, with no cessation of blood flow during the 30-min observation period. Intravenous administration of ER-410660 (0.6, 2, and 6 mg/kg) to rats treated with ASA (10 mg/kg) did not significantly increased when compared with ASA alone, even at the highest dose. In conclusion, a TF/FVIIa inhibitor suppressed arterial thrombosis without affecting the bleeding time associated with ASA. Owing to these favorable characteristics, anticoagulation via TF/FVIIa inhibition may be a superior approach to the prophylaxis of atherothrombotic diseases.