Tetrapeptide derived inhibitors of complexation of a class II MHC: the peptide backbone is not inviolate.

Major histocompatabilty (MHC) proteins rely heavily on peptide backbone recognition for ligation. Nonetheless, modifications to the polyamide backbone of a tetrapeptide ligand can be made without abrogating binding.

Tetrapeptide derived inhibitors of complexation of a class II MHC: fully unnatural ligands.

Tetrapeptide derived major histocompatability (MHC) II ligands have been developed that contain no unadulterated peptide bonds. These are the 'least peptidic' ligands for any MHC protein yet reported.

Selective protection and relative importance of the carboxylic acid groups of zaragozic acid A for squalene synthase inhibition.

Chemistry that allows selective modification of the carboxylic acid groups of the squalene synthase inhibitor zaragozic acid A (1) was developed and applied to the synthesis of compounds modified at the 3-,4-,5-,3,4-,3,5-, and 4,5-positions. A key step in this procedure is the selective debenzylation by transfer hydrogenolysis in the presence of other olefinic groups. These compounds were tested in the rat squalene synthase assay and in vivo mouse model. Modification at C3 retains significant enzyme potency and enhances oral activity, indicating that C3 is not essential for squalene synthase activity. Modification at C4 and C5 results in significant loss in enzyme activity. In contrast, substitution at C3 or C4 enhances in vivo activity. Furthermore, disubstitution at the C3 and C4 positions results in additive in vivo potency.

Development, synthesis, and biological evaluation of (-)-trans-(2S,5S)-2-[3-[(2-oxopropyl)sulfonyl]-4-n-propoxy-5-(3- hydroxypropoxy)-phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran, a potent orally active platelet-activating factor (PAF) antagonist and its water-soluble prodrug phosphate ester.

(-)-trans-(2S,5S)-2-[3-[(2-Oxopropyl)sulfonyl]-4-n-propoxy-5-(3- hydroxypropoxy)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (10) is one of the most potent platelet-activating factor (PAF) antagonists in vitro and in vivo developed to date. This diaryltetrahydrofuran derivative evolved from modifications of MK 0287 which has been evaluated in clinical studies for asthma. Two structural modifications of MK 0287 were made: (1) elaboration of the 3'-[(hydroxyethyl)sulfonyl] group to a beta-keto propylsulfonyl, and (2) replacement of the 5'-methyl ether by a 3-hydroxypropyl ether. Compound 10 potently and specifically inhibits the binding of [3H]-C18-PAF to human platelet membranes (Ki 1.85 nM) and PMN membranes (Ki 2.89 nM). In vivo, 10 inhibits PAF-induced plasma extravasation and elevated N-acetyl-beta-D-glucosaminidase (NAGA) levels in male rats with ED50 values of 60 micrograms/kg, po and 4 micrograms/kg, iv respectively, and inhibits PAF-induced bronchoconstriction in guinea pigs with an ED50 value of 15 micrograms/kg after intraduodenal administration. Compound 15, a water-soluble phosphate ester prodrug derivative of 10 is at least equipotent to 10 in the in vivo models. Compound 19S, the primary and major metabolite of 10 and 15, is equipotent in in vitro and in vivo models.

(+/-)-trans-2-(3-Methoxy-5-methylsulfonyl-4-propoxyphenyl)-5-(3,4,5- trimethoxyphenyl)tetrahydrofuran (L-659,989), a novel, potent PAF receptor antagonist.

The title compound, L-659,989, is a highly potent, competitive, and selective antagonist of the binding of [3H]PAF to its receptors in platelet membranes from rabbits and humans. It exhibits equilibrium inhibition constants for PAF binding of 1.1 nM (rabbit) to 9.0 nM (human), values that are at least 1-2 orders of magnitude lower than those of other PAF antagonists tested. L-659,989 potently inhibits PAF-induced aggregation of rabbit platelets and degranulation of rat (ED50 4.5 nM) and human (ED50 10 nM) neutrophils. L-659,989 inhibits PAF-induced extravasation and lysosomal enzyme release in rats, and is active orally in female rats (ED50 0.2 mg/kg) with an extraordinary oral duration of action of 12 to 16 hours at 1.0 mg/kg p.o.