Douglas W. Beight

Novel antihypertensive agent

Coronary heart disease and cerebrovascular disease continue to be the leading causes of illness and death among adults from developed countries. Their prevalence is strongly related to the effects of many different risk factors, including high blood pressure, cigarette smoking, dyslipidaemia and diabetes. The management of cardiovascular (CV) risk factors should be viewed as an integrated strategy of intervention aimed at correcting as many of the underlying causes of CV disease as possible. Blocking the renin–angiotensin–aldosterone system with new, well-tolerated antihypertensive drugs, and blood pressure regulation by means of new drugs that also reduce plasma cholesterol levels or improve insulin resistance and glucose tolerance, could lead to a reduction of CV diseases.

The synthesis of fluorinated aminophosphonic acid inhibitors of alanine racemase

Abstract The synthesis of β-trifluoro, β-difluoro, and β-monofluoro-1-aminoethanephosphonic acids is described utilizing fluorinated acetic acids as tarting materials.

A dehydroalanine route to an activated phenolic sparsomycin analog

Abstract The addition of p-mercaptophenol to an N-protected dehydroalanine methyl ester is utilized in the synthesis of novel activated sparsomycin analog MDL 20,093.

The conversion of a diazolactam to an α-methylenelactam: An entrance to new conformationally restricted inhibitors of angiotensin-converting enzyme

Abstract Methodology for the conversion of an α-aminolactam dipeptide mimic to an α-methylenelactam derivative was developed utilizing the decomposition of an α-diazolactam intermediate in the presence of triphenylphosphine as the key step. Conjugate addition of thiolbenzoic acid to the derived unsaturated lactam and deesterification gave two new potent sulfhydryl containing inhibitors of angiotensin-converting enzyme.

“An efficient synthesis of ethyl (R)-2-hydroxy-4-phenylbutyrate: A useful intermediate in the synthesis of converting enzymeinhibitors”

Abstract Optically pure Ethyl (R)-2-hydroxy-4-phenylbutyrate has beensynthesized stereoselectively in 24% overall yield.

SYNTHESIS OF CONSTRAINED THIORPHAN ANALOGS AS INHIBITORS OF NEUTRAL ENDOPEPTIDASE

Abstract Constrained derivatives of thiorphan were prepared and found to be potent inhibitors of neutral endopeptidase 24.11.

Interaction of Angiotensin I-Converting Enzyme with Two Potent Tricyclic Inhibitors

Inhibition of rabbit lung angiotensin I-converting enzyme was studied with two inhibitors that combined tricyclic mimics of a substrate C-terminal dipeptide recognition unit with a 4-phenylbutanoic acid fragment. The overall inhibition constant for [4S-[4 alpha, 7 alpha(R*),12b beta]]-7-[S-(1-carboxy-3-phenylpropyl) amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a] [2] benzazepine-4-carboxylic acid (MDL 27,088) was approximately 4 pM, whereas that for [4R-[4 alpha, 7 alpha(S*), 12b beta]]-7-[S-(1-carboxy-3-phenylpropyl)amino]-3,4,6,7,8, 12b-hexahydro-6-oxo-1H-[1,4]thiazino[3,4-a] [2]benzazepine-4-carboxylic acid (MDL 27,788) was estimated to be 46 pM. The formation of an initial complex of target enzyme and MDL 27,088 and its slower isomerization to a second complex were characterized kinetically. Both compounds appear to be among the most potent inhibitors known for this enzyme.