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Biomedical subjects

W A Metz

Publications and source records attributed to W A Metz.

8 recordsLinked to original sources
PubMed2000

Soluble polymer-supported chemoenzymatic synthesis of the C(21)-C(27) fragment of the bryostatins.

A chemoenzymatic synthesis of the C(21)-C(27) fragment of the marine macrolide family of bryostatin antibiotics is presented. The approach commences from achiral starting materials and has as its crucial step the enzymatic resolution of a racemic mixture of soluble polymer-supported alcohols (syn-10 and syn-11). The immobilized lipase from Candida antarctica (Novozym 435) catalyzes the enantioselective acetylation of syn-10 (in 40% conversion and >99% ee), allowing isolation of the key intermediate (R)-14 in enantiomerically pure form following its cleavage from the poly(ethylene) glycol (PEG) scaffold. The PEG matrix is both compatible with the multipolymer enzymatic transformation and allows for rapid purification and facile NMR characterization of all intermediates throughout the synthesis.

Bryostatins↗
PubMed1998

A simple method for coupling aldehydes to solid support.

A new method for attaching aldehydes to solid supports has been developed employing a 2,2-bis(hydroxymethyl)propionic acid (DMPA) functionalized resin. High loading levels are obtained for both aryl and alkyl aldehydes protected as their respective acetals. Treatment of the derivatized resin with 95% TFA then cleanly affords the recovered aldehyde in high yield.

Aldehydes↗
PubMed1998

Inhibition of human neutrophil elastase. 4. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of P2-modified, orally active peptidyl pentafluoroethyl ketones.

A series of P2-modified, orally active peptidic inhibitors of human neutrophil elastase (HNE) are reported. These pentafluoroethyl ketone-based inhibitors were designed using pentafluoroethyl ketone 1 as a model. Rational structural modifications were made at the P3, P2, and activating group (AG) portions of 1 based on structure-activity relationships (SAR) developed from in vitro (measured Ki) data and information provided by modeling studies that docked inhibitor 1 into the active site of HNE. The modeling-based design was corroborated with X-ray crystallographic analysis of the complex between 1 and porcine pancreatic elastase (PPE) and subsequently the complex between 1 and HNE.

Administration, Oral↗
PubMed1995

Inhibition of human neutrophil elastase. 3. An orally active enol acetate prodrug.

Several analogs of N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N-[3,3,4,4,4-penta fluoro-1- (1-methylethyl)-2-oxobutyl]-L-prolinamide (1), in which the chiral center of the P1 residue has been eliminated, were synthesized and tested as inhibitors of human neutrophil elastase (HNE). Observations made during the course of this work led to the development of a single-step, stereoselective synthesis of E-enol acetate derivatives from HNE inhibitors containing a mixture of epimers at P1. In vitro studies, in the presence of added esterase, and 19F NMR studies, in biological media, indicated that the E-enol acetate derivatives should act as prodrugs in vivo. The ED50 value for (E)-N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N-[2- (acetyloxy)-3,3,4,4,4-pentafluoro-1-(1-methylethyl)-1-buteny l]-L-prolinamide (20), when administered orally in the hamster lung hemorrhage model, was 9 mg/kg.

Acetates↗
PubMed1976

Construction of a practical and inexpensive air stimulator for caloric vestibular testing.

An inexpensive and practical method for delivering air into the aural canal at a selected stable temperature is described. A water-air heat exchanger utilizing the external circulation of a constant-temperature water bath brings the temperature of the air stream to a chosen value. Measurements indicate stable air outflow temperatures are maintained when proper nozzle design and air flow rates are employed. The apparatus is easy to construct and has proven convenient and effective when used in the clinical vestibular laboratory.

Air↗
PubMedDate not supplied

Results of new air caloric testing method among normal subjects. I. Biphasic testing.

A new air caloric testing method is described in which the temperature of a continuous aural irrigation is switched hot and cold values at times calculated to control the intensity of the resulting vestibular stimulation. Applications of low or high caloric stimulus intensities to normal subjects were well tolerated and reliably produced appropriate low or high intensity nystagmic responses. Nystagmus intensity values obtained from this study were compared with predicted intensity values from a computerized simulation of the actual test conditions, and also with values obtained when using biphasic water irrigations. As a result, further improvements in our methodology have been effected.

Air↗