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The structural optimization for binding affinity and attempted modification of agonist function of a nonpeptide ligand of the human C5a receptor is described.

Studies detail the formation and utility of bridged ethers of bicyclo[5.4.0]undecanes as a means for stereocontrolled functionalization as described in a survey of conjugate additions, reductions, and oxidative cyclizations. The intramolecular dipolar cycloaddition of 3-oxidopyrylium ylides affords a facile preparation of the starting trans-fused bicyclo[5.4.0]undecenone 1. Efficient methods toward highly oxygenated bicycloundecanes are described via the highly selective reductive cleavage of 12-oxatricyclo[6.3.1.0(1,6)]dodecanes such as 20 and 21. Reclosure of the era-bridge was examined. Vanadium-catalyzed oxidative reclosure of 24 led exclusively to the novel 2-oxatricyclo[5.4.1.0(3,8)]dodecane system 31.

We present the design, syntheses, and in vitro biological data of a series of substituted quinazolinone containing, AT1 selective, Angiotensin II (AII) receptor antagonists. Substituents at the 6-position of the quinazolin-4(3H)-ones 3 have pronounced effects on the vitro potency related to both their electronic and lipophilic character.

The biphenyl fragment of the potent angiotensin II receptor antagonist L-158,809 was replaced by a phenylthiophene and a phenylfuran moiety. Replacement of the tetrazole-bearing phenyl by a thiophene resulted in a small loss in binding affinity (< 3X). Replacement of the central phenyl ring by a 2,5-disubstituted thiophene resulted in a thousand fold loss of potency.

The structure activity relatoionship, linear regression analysis and in vivo evaluation of a series of substituted 2-butyl-3-[(2′-tetrazol-5-yl)biphen-4-yl)methyl]quinazolin-4(1H)-ones as antagonists of the AT1 receptor for angiotensin II is presented. L-159,093 (2-butyl-6-(N-isopropyl-N-methyl-carbamoyl)amino-3-[(2′-tetrazol-5-yl)biphen-4-yl)methyl]quin azolin-4(1H)-one (IC50=0.1nM rabbit aorta) is shown to be a potent orally active AII antagonist in rats and rhesus.

Transformations derived from [3+2]-intramolecular cycloaddition of a 3-oxidopyrylium ylide lead to the bicycloundecanone 19 .

AbstractThe aldehydes (I) form semiacetals, e.g. (III), with alcohols such as methanol (II).