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A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists.

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Six cases of primary glomeruionephritis with predominant IgG deposits in the mesangium are described on the basis of a review of renal-biopsy-proven 1,116 cases with primary glomeruionephritis between 1977 and 1990. All patients were female (6-52 years old). Six patients appeared with microscopic hematuria: 3 with episodes of gross hematuria and 3 with mild proteinuria, but none with the nephrotic syndrome. Renal function was normal except for 1 case (52 years old) complicated with hypertension. Serum levels of immunoglobulins and complements were almost normal. Morphologically minor or focal/segmental glomerular alterations were observed. Immunofluorescence showed that pure mesangial IgG deposition was characterized in all cases, whereas no IgA nor IgM was found in any of them. Mesangial deposition of C3 and C1q was observed in 4 and 3 cases, respectively. Electron microscopy revealed dense deposits within the mesangial area in all cases. The clinical course was benign, and the complication with systemic diseases like a rheumatic disease was not observed. This primary glomeruionephritis is an entity characterized by low incidence in Japan, mild abnormalities in urinalysis, minor glomerular alterations with predominant mesangial IgG deposits and a relative benign course.