For over three decades, renal physiology has sought a putative natriuretic hormone (third factor) that might control the body's pool of extracellular fluid, an important determinant in hypertension, congestive heart failure, and cirrhosis. In our search for this hormone, we have isolated several pure natriuretic factors from human uremic urine that would appear, alone or in combination, to mark a cluster of phenomena previously presumed to be that of a single "natriuretic hormone." This paper reports the purification, chemical structure, and total synthesis of the first of these compounds, LLU-a, which proved to be 2,7,8-trimethyl-2-(pcarboxyethyl)-6-hydroxychroman, presumably a metabolite of y-tocopherol. Both natural LLU-a and synthetic material are identical (except for optical activity) with respect to structure and biological activity. It appears that the natriuretic activity of LLU-a is mediated by inhibition of the 70 pS K+ channel in the apical membrane of the thick ascending limb of the kidney.As a result of salt-induced plasma-volume expansion in mammals, three concurrent events have been observed: sustained natriuresis, rising plasma concentration of a Na+ transport inhibitor, and pressor activity. It has been presumed that these effects are due to elaboration of a low-molecular-weight "natriuretic hormone," the putative controller of extracellular fluid (1). Over 30 years of effort have failed to characterize the putative hormone (2, 3). Atrial natriuretic factor, when infused, produces a natriuresis and a decrease in blood pressure that are short-lived (4, 5) and whose physiological role is still undefined (6, 7).The approach of essentially all other workers has been to investigate mammalian-derived isolates that inhibit the Na+ pump (2,8). From these studies, digoxin (9) and "iso-ouabain" (10-13) have been isolated; however, digoxin and ouabain lead to kaliuresis (4,(14)(15)(16)(17). Therefore, we hypothesized that this search tool is an inadequate marker for natriuresis. Consequently, a natriuretic assay has been developed in which the in vivo physiological events, urine volume, K+ and Na+ concentrations, and mean arterial pressure are measured (18).In this paper, we report the isolation of pure LLU-a, the determination of its structure by spectroscopy, its synthesis in racemic form, and its biological characterization. Given its structure, we infer that it is the product of in vivo oxidative metabolism of y-tocopherol, a member of the vitamin E complex. MATERIALS AND METHODSPurification of LLU-a. Human uremic urine (800 liters) was collected, processed by ultrafiltration (3 kDa) and lyophilization, and then chromatographed on Sephadex G-25 to obtain the post-salt fraction as described (18 Step 1. Reversed-phase HPLC was performed by gradient elution with 0.2 M pyridinium acetate, pH 5.5, and methanol as described (4). Based on bioassay data, fractions 50-80 were combined for further purification.Step 2. The next column (5 pm; 10 x 250 mm) was eluted at 2 ml/min with a gradient formed from...

Phosphoinositide 3-kinase α (PI3Kα) is a lipid kinase that plays a key regulatory role in several cellular processes. The mutation or amplification of this kinase in humans has been implicated in the growth of multiple tumor types. Consequently, PI3Kα has become a target of intense research for drug discovery. Our studies began with the identification of benzothiazole compound 1 from a high throughput screen. Extensive SAR studies led to the discovery of sulfonamide 45 as an early lead, based on its in vitro cellular potency. Subsequent modifications of the central pyrimidine ring dramatically improved enzyme and cellular potency and led to the identification of chloropyridine 70. Further arylsulfonamide SAR studies optimized in vitro clearance and led to the identification of 82 as a potent dual inhibitor of PI3K and mTOR. This molecule exhibited potent enzyme and cell activity, low clearance, and high oral bioavailability. In addition, compound 82 demonstrated tumor growth inhibition in U-87 MG, A549, and HCT116 tumor xenograft models.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximately 30% of the gained affinity between "flexible" 4 (Ki = 132 nM) and "rigid" 28 (Ki = 0.77 nM) to decreased conformational entropy.