Synthesis, antiviral activity, and bioavailability studies of gamma-lactam derived HIV protease inhibitors.

Incorporation of a gamma-lactam in hydroxyethylene isosteres results in modest inhibitors of HIV-1 protease. Additional structural activity studies have produced significantly more potent inhibitors with the introduction of the trisubstituted cyclopentane (see compound 20) as the optimum substituent for the C-terminus. This new amino acid amide surrogate can be readily prepared in large scale from (R)-pulegone.

Development of 1,4-benzodiazepine cholecystokinin type B antagonists.

A series of 3-(arylureido)-5-phenyl-1,4-benzodiazepines, nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK), are described. Derived by reasoned modification of the CCK-A selective 3-carboxamido-1,4-benzodiazepine, MK-329, this paper chronicles the development of potent, orally effective compounds in which selectivity for the CCK-B receptor subtype was achieved. The principal lead structure that emerged from these studied is L-365,260, a compound which has been submitted for clinical evaluation.

Development of a novel class of cyclic hexapeptide oxytocin antagonists based on a natural product.

A new structural class of cyclic hexapeptide oxytocin antagonists derived from Streptomyces silvensis and typified by L-365,209 (cyclo-[L-prolyl1-D-phenylalanyl2-L- isoleucyl3-D-dehydropiperazyl4-L-dehydroperazyl5-D-(N- methyl)phenylalanyl6]) was recently reported. In this paper we further delineate the structure-activity profile for this new class by systematic study of L-365,209 analogs obtained by total synthesis. The optimal combination of cyclic amino acid ring sizes at positions 1, 4, and 5 and the role of the N-alkyl substituent at position 6 was elucidated.

Novel glutamic acid derived cholecystokinin receptor ligands.

Novel aryl amide analogues of glutamic acid dialkylamide have been synthesized to test for a possible structural analogy between glutamic acid and benzodiazepine CCK antagonists such as compounds 2 and 24 (lorglumide and MK-329, respectively). In support of the structural model, certain of these hybrid compounds are more potent in pancreas CCK radioligand binding assays than corresponding lorglumide-type reference compounds. Modifications previously found in the benzodiazepine antagonists to result in brain CCK/gastrin receptor selectivity were also incorporated to produce an aryl urea series of glutamic acid analogues.

Cholecystokinin-A receptor ligands based on the kappa-opioid agonist tifluadom.

Tifluadom, a kappa-opioid agonist and cholecystokinin-A (CCK-A) receptor antagonist, was utilized as a model to prepare a series of 2-(aminomethyl)- and 3-(aminomethyl)-1,4-benzodiazepines. These compounds were tested in vitro as inhibitors of the binding of [125I]CCK to rat pancreas and guinea pig brain receptors. All compounds with IC50's less than 100 microM proved to have greater affinity for the CCK-A receptor, with the most potent analogue, 6e, having an IC50 of 0.