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Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds 1 and 20 bound to human 11beta-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11beta-HSD1 inhibition may be a valid target for the treatment of diabetes.

There are three areas to consider when designing/implementing wire bonding to advanced ULSI damascene-copper chips having copper metallization and low dielectric-constant polymers embedded beneath them (Cu/LoK). These are: 1) the copper-pad top-surface oxidation inhibitor coating - metal/organic/inorganic. (Current work involves evaluating the metal and inorganic options); 2) the low dielectric constant materials available; 3) under-pad metal/polymer stacks and support structures necessary for bondability and reliability. There are also various polymer/metallurgical interactions, resulting in long term packaged-device reliability problems, that can occur as the result of the wire bonding process over low modulus, LoK materials with barriers. These include cracked diffusion barriers, copper diffusion into the LoK polymers, cracking/spalling/crazing of the LoK materials, and bond pad indentation ("cupping"). Low-K polymer materials, with high expansion coefficients and low thermal conductivities, can also increase the stress and further extend any existing damage to barriers. Well designed LoK and the underpad structures should have no negative effect on bonding parameters and be invisible to the bonding process.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive glucocorticoid cortisone to its active form, cortisol. The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. Herein, the structure-activity relationship of a series of piperazine sulfonamide-based 11β-HSD1 inhibitors is described. (R)-3,3,3-Trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)sulfonyl)thiophen-2-yl)-2-hydroxypropanamide 18a (HSD-621) was identified as a potent and selective 11β-HSD1 inhibitor and was ultimately selected as a clinical development candidate. HSD-621 has an attractive overall pharmaceutical profile and demonstrates good oral bioavailability in mouse, rat, and dog. When orally dosed in C57/BL6 diet-induced obesity (DIO) mice, HSD-621 was efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, HSD-621 was well tolerated in drug safety assessment studies.

The project objective was to determine the effects of production procedures on the characteristics of electroless nickel coatings. Deposition rate, phosphorus content, hardness, appearance, and metal distribution are reported for deposits from several hypophosphite type electroless nickel baths, both proprietary and non-proprietary. The baths were operated under a variety of conditions with variations of composition. Extensive data are given on the relation of deposit hardness to phosphorus content and to heat treatment at 100, 200, and 400 C. Some data are given relative to electroless Ni-B, Ni-P-Cu, and Ni-P-Mn alloys.

This paper is the third published report on the results of a broad program on properties of electrodeposited copper, sponsored jointly by the American Electroplaters' Society, The International Copper Research Association, Inc., The Copper Development Association, and the National Bureau of Standards. The first paper is a comprehensive review of the literature to 1965. The second paper is an interim report on experimental results. The present and final paper, which incorporates the data in the second, includes data from the baths designated in the title, for deposits prepared under a wide range of operating conditions and with use of a variety of addition agents. Properties measured include tensile strength, yield strength, elongation, modulus of elasticity, fatigue strength, hardness, internal stress, density, electrical resistivity, and thermal expansivity. Properties were measured for as‐plated deposits, deposits after annealing at several temperatures, after cold‐working, and at low and high ambient temperatures. Structure of deposits was examined by optical, electron micrograph, and x‐ray methods. Content of impurities in deposits was determined. Correlations are developed among properties, structure, impurity content, type of bath, and operating conditions.