Search

HER-2 belongs to the ErbB family of receptor tyrosine kinases, which has been implicated in a variety of cancers. Overexpression of HER-2 is seen in 25–30% of breast cancer patients and predicts a poor outcome in patients with primary disease. Trastuzumab (Herceptin), a monoclonal antibody to HER-2, is specifically approved for HER-2-positive breast cancer but is active only in a subset of these tumors. Blocking HER-2 function by a small molecule kinase inhibitor, therefore, represents an attractive alternate strategy to inhibit the growth of HER-2-positive tumors. HKI-272 is a potent inhibitor of HER-2 and is highly active against HER-2-overexpressing human breast cancer cell lines in vitro. It also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. HKI-272 reduces HER-2 receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor. In agreement with the predicted effects of HER-2 inactivation, HKI-272 treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory pathways. This leads to arrest at the G1-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle, ultimately resulting in decreased cell proliferation. In vivo, HKI-272 is active in HER-2- and EGFR-dependent tumor xenograft models when dosed orally on a once daily schedule. On the basis of its favorable preclinical pharmacological profile, HKI-272 has been selected as a candidate for additional development as an antitumor agent in breast and other HER-2-dependent cancers.

A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

1s-2p Lyman {alpha} transitions in hydrogenic iron Fe{sup 25+} have been observed from a beam-foil source in fourth-order diffraction off ADP 101 and PET 002 crystals, simultaneously with the n=2 to n=4 Balmer {beta} transitions diffracted in first order. Calibration of the local dispersion relation of the spectrometer using Balmer {beta} lines provides measurements of Lyman {alpha} wavelengths. The approach of fitting the full two-dimensional dispersion relation, including other members of Balmer and Lyman series, limits random and systematic correlation of parameters, and reveals a major systematic due to dynamical diffraction depth penetration into a curved crystal. The development of a theory of x-ray diffraction from mosaic crystals was necessary for the accurate interpretation of the experimental data. Photographic theory was also developed in the process of this research. Several systematics are discussed and quantified for the first time for these medium-Z QED comparisons. 2s-1s and 4f-2p satellites are explicitly investigated, and a dominant systematic is uncovered, which is due to the variable location of spectral emission downstream of the beam-foil target. 1s-2p{sub 3/2}, 1s-2p{sub 1/2} iron Lamb shifts are measured to be 35 376{+-}1900 cm{sup -1} and 35 953{+-}1800 cm{sup -1}. These agree with but lie higher than theory.more » This represents a 5.7% measurement of the hydrogenic 1s-2p{sub 1/2} Lamb shift in iron. The technique also reports the iron 2p{sub 3/2}-2p{sub 1/2} fine structure as 171 108 cm{sup -1}{+-}180 cm{sup -1}, which represents a 51% measurement of the hydrogenic iron fine-structure Lamb shift, and reports measurements of secondary lines.« less

Agents that inhibit P-glycoprotein may restore sensitivity to some antitumor drugs in cancer patients. Optimization of the specificity and potency of one class of chemosensitizing agents related to verapamil has led to the identification of alpha-(3,4-dimethyoxyphenyl)-3,4-dihydro-6, 7-dimethoxy-alpha-[(4-methylphenyl) thio]-2(1H)-isoquinolineheptanenitrile, designated CL 329,753. In vitro, 0.1 to 2.0 microM CL 329,753 restored sensitivity to drugs in the multidrug resistance (MDR) phenotype in cell lines that overexpress P-glycoprotein. CL 329,753 was greater than 10-fold more potent and efficacious than cyclosporine A or verapamil in vitro, particularly in cells that express high levels of P-glycoprotein. The enhanced activity of CL 329,753 may be related to its inability to be transported by P-glycoprotein, since low drug accumulation of cyclosporine or verapamil but not CL 329,753 was found in P-glycoprotein-containing cells, yet all three agents inhibited vinblastine binding to membranes containing P-glycoprotein and inhibited photoaffinity labeling of P-glycoprotein. In vivo, CL 329,753 resensitized drug-resistant tumors to vinblastine or doxorubicin in an ascitic or solid tumor model, respectively. No alteration in the plasma pharmacokinetic profile of doxorubicin by CL 329,753 has been found. Furthermore, the compound had 70-fold less calcium channel antagonistic activity compared with verapamil.

The role of immunologically released mediators, such as histamine, leukotrienes, and platelet-activating factor, is well-established for asthma and other allergic disorders. Developing therapeutic agents which would block mediator release from mast cells and other relevant cell types would provide a rational approach to asthma therapy. Using human basophil as a screen, a series of 4-aryl-2-(phenylamino)pyrimidines was found which inhibited mediator release. These compounds were prepared by condensing acetyl heterocycles with dimethylformamide dimethyl acetal to form enaminones which are cyclized with aryl guanidines to give pyrimidines. After examining a large number of analogs, N-[3-(1H-imidazol-1-yl)phenyl]-4-(2-pyridinyl)-2- pyrimidinamine (1-27) was chosen for toxicological evaluation.

With the use of the human basophil histamine release assay, 5-aryl-2-amino[1,2,4]triazolo[1,5-c]pyrimidines were found to be active as mediator release inhibitors. These compounds were prepared by reacting arylamidines with sodium ethyl formylacetate or with ethyl propiolate to give pyrimidinones. Treatment with phosphorus oxychloride gave a chloropyrimidine, which was converted to a hydrazinopyrimidine with hydrazine. Cyclization, using cyanogen bromide, gave the triazolo[1,5-c]pyrimidines, after a Dimroth rearrangement. Following a structure-activity evaluation, the 5-[3-(trifluoromethyl)phenyl]-2-amino (8-10), 5-(3-bromophenyl)-2-amino (8-13), 5-[3-(difluoromethoxy)-phenyl]-2-amino (8-11), and 5-(4-pyridinyl)-2-amino (6-7) compounds were found to have the best activity. They were chosen for further pharmacological and toxicological study.

Measurements of mean velocity and turbulence intensity components are reported for flow over a two-dimensional rectangular depression; these include measurements in the highly turbulent regions of recirculating flow. Predictions of the mean-flow variables were obtained from three finite-difference models: (1) a vorticity stream-function model using constant effective viscosity, (2) a primitive variable model using constant effective viscosity, and (3) a primitive variable model in which effective viscosity is computed from a turbulence model. The turbulent kinetic energy was also predicted by the last of these models. These predictions were compared with the measurements in order to evaluate what accuracy can be expected when state-of-the-art finite-difference models are applied to complex flow situations in the atmospheric environment. Some areas are noted where improvement of modeling capabilities for complex flows is still needed.

3-Ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (2) was converted to 6-carbethoxymethyl-3-ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (6) through an oxalyl derivative. Treatment of 6 with ammonia gave the corresponding amide 7 which on sodium borohydride reduction and subsequent dehydration yielded 6-carbamylmethyl-3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (9). The analogous ester 10 was similarly obtained from 6. Numerous attempts to dealkylate the 3-ethoxy group of 9 or 10 failed. However, 6 coould easily be dealkylated on heating with 25% hydrochloric acid in a sealed tube.The ester, 6-carbethoxymethyl-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinoline-3(2H),5-dione (11), so obtained was converted to the corresponding amide 12 which on reduction with sodium borohydride and subsequent dehydration afforded the desired compound, 6-car-bamylmethyl-8-methyl-7(5)H-cyclopental[f]isoquinolin-3-(2H)-one (1). 1 was found to be mildly cytotoxic againstL5178Y mouse leukemia cells in culture.1 was also found to bind to native calf thymus DNA. 1 inhibited RNA synthesis by a DNA-dependent RNA polymerase and a higher inhibition of RNA synthesis was observed when poly(dG-dC) was used as a template than when poly(dA-dT) was used. A significant increase of thermal transition temperature of calf thymus DNA and poly(dG)-poly(dC) was observed in the presence of 1. The accumulated evidence demonstrates that 1 interacts weakly with calf thymus DNA and interacts preferentially with poly(deoxyribonucleotides)-containing GC pairs.

dl-Erythro-16-methoxy-PGE2, PGA2, PGF2alpha, 11-deoxy PGE1, and 11-deoxy PGF1alpha have been prepared via the cuprate conjugate addition procedure. These congeners are less potent than the parent prostaglandins as stimulators of isolated gerbil colon contractions and as bronchodilators in the guinea pig Konzett assay.

By the use of space-filling models, a novel compound, 6-carbamylmethyl-8-methyl-7(5)H-cyclopenta[f]isoquinolin-3-(2H)-one was devised which would be expected to hydrogen bond specifically to GC pairs in the major groove of the double helix such that (i) the amino group of the cytosine molecule donates a hydrogen bond to the C-3 carbonyl of the isoquinoline moiety and (ii) the amide proton of the side chain donates a hydrogen bond to the N-7 of guanine. 3-Ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (4) which constitutes the basic ring system of 1 was synthesized in a multistep procedure starting from m-methyl-N-acetylbenzylamine (5). Friedel-Crafts reaction of 5 led to 2,4-bis(chloromethyl)-5-methyl-N-acetylbenzylamine (6) which on treatment with KCN, hydrolysis of the resultant nitrile, and subsequent esterification afforded 6-carbethoxymethyl-7-methyl-1,2,3,4-tetrahydroisoquinolin-3-one (9). Treatment of 9 with triethyloxonium fluoborate followed by dehydrogenation of the product gave 6-carbethoxy-methyl-3-ethoxy-7-methylisoquinoline (14). Chain extension of 14 followed by cyclization led to 3-ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (19) which on reduction and subsequent dehydration yielded 3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (4).

Following power run-14 on the Sodium Reactor Experiment, 13 of the 43 fuel elements were found to he damaged. An Ad Hoc Committee was established to assist in determiring the source of the difficulty, to review and advise on steps taken to return the reactor to operation, and to recommend any necessary changes in the reactor system or in operating procedures to avoid a recurrence. An, Iterim Report was issued which presented the evidence available at that time as to the cause of the damage. Included is the concluding report of the Ad Hoc Committee. The conclusion as to cause of the fuel element failures was modified on the basis of data developed since the first report was written. Several modifications were made to the reactor system to avoid a recurrence. (auth)

Excerpt More than a hundred years ago Laennec described both tuberculosis and chronic obstructive emphysema, but without relating them to each other.1-2Subsequently, a relationship between these di...

This paper begins with a statement of the acceptance and use of inertia welding in the gas turbine field. A short explanation of the inertia welding process follows. Categories of welds discussed are solid inertia butt welds; tubular inertia butt welds; and angular-annular inertia butt welds. An example of the first category is a bimetallic engine valve. The second category is typified by steel shafts joined to superalloy rotors for turbines. The joining of wrought superalloy disks to cast superalloy blade rings to produce a composite wheel comes into the third category. The effect of welding parameters on strength and microstructure, as well as design and process changes required for inertia welding are related. In conclusion, basic considerations for utilization of inertia welding are expressed.Copyright © 1971 by ASME

Excerpt It is increasingly evident that a diffuse obstructive pulmonary syndrome is often associated with tuberculosis.1, 2A considerable number of patients in sanatoria require treatment for chron...

As a part of the growing awareness of the syndrome of diffuse pulmonary ventilatory obstruction, numerous studies of the epidemiology of this disease have been carried out, particularly in the industrial countries of the northern temperate zone. Numerous problems have arisen, particularly in regard to selection of appropriate physiologic tools for the determination of ventilatory obstruction and also in interpretation of obtained data. As an illustrative example, the methods and findings of one of these studies will be presented and discussed in comparison with previously reported studies. Because of increasing evidence that a diffuse obstructive pulmonary syndrome plays a major role in the diagnosis and care of patients in a tuberculosis hospital (1, 2), a study of the incidence of this syndrome was undertaken (3, 4), utilizing the measurement of maximal expiratory flow by the "Puffmeter" of Goldsmith (5). The results of this investigation are published elsewhere" and may be summarized as follows