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A series of 2-(biphenylmethyl)glutaric acid amide derivatives were synthesized and evaluated for NEP inhibitory activity. The mode of inhibitor-enzyme interactions of the most potent compound 3a, with a thiazolylacetic acid group at the P2' position, was evaluated by a computer analysis.

Summary Molecular modeling of a complex between factor Xa (FXa) and DX-9065a, a novel FXa inhibitor, has demonstrated a salt-bridge interaction of the amidinonaphthalene moiety of the inhibitor to the S1 site pocket of the enzyme and a crucial carboxyl group of the inhibitor for the FXa/thrombin selectivity. In the present study, we synthesized some DX-9065a derivatives and studied their interaction modes with FXa, trypsin and thrombin to evaluate the role of the acetimidoylpyrrolidine moiety. The docking study of the inhibitor in the FXa model provided a molecular model of the inhibitor-FXa complex showing a hydrophobic interaction of the pyrrolidine ring with an aryl binding site of FXa, and a hydrogen bond between the acetimidoyl group and the backbone carbonyl oxygen of Glu97. Comparison between the interaction mode of DX-9065a with FXa and those with trypsin and thrombin explained the inhibitory potencies of the enzymes.

Since factor Xa (fXa) plays a pivotal role in the blood coagulation cascade, inhibition of fXa is thought to be an effective treatment for a variety of thrombotic events. (2S)-2-[4-[[(3S)-1-Acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (DX-9065a) was previously found in our laboratory as a novel orally active factor Xa inhibitor. DX-9065a exhibits a strong inhibitory activity toward fXa by occupying the substrate recognition (called S1) sites and aryl binding sites of fXa. Herein we describe conversions of the amidinonaphthalene and the acetimidoylpyrrolidine moieties of DX-9065a. Some compounds showed remarkably increased in vitro anti-factor Xa and PRCT activities compared with those of DX-9065a. The most promising compound 38 showed four times the prolongation of APTT against DX-9065a after oral administration to rats.

A series of carboxylate compounds were prepared from N(alpha)-substituted 2,3-diaminopropionic acid and were tested for efficacy as matrix metalloproteinase (MMP) inhibitors. During modeling of the initial compound 10a, we utilized three-dimensional structure modeling software (InsightII/Discover Ver. 2.98). Some of the prepared carboxylate derivatives, such as carbamate compounds (12c,d, 22) and sulfonamide compounds (14b,c), proved to be effective MMP-1 inhibitors (with IC50 values of a 10(-6) M order), depending on the substituent at the N(alpha)-position of 2,3-diaminopropionic acid. Some of them were also evaluated for inhibition of stromelysin-1 (MMP-3), and the sulfonamide compound 14c exceeded the lead compound 5b in its MMP-3 inhibitory potency. For the carbamate compounds, we investigated the minimum molecular size at which the MMP-1 inhibitory potency was maintained, and found that this was P3-P1' compound 10b.

Di- and tri-substituted [(4-oxo-4H-1-benzopyran-7-yl)oxy]acetic acids, and 4-oxo-3-phenyl-4H-furo[2,3-h]-[1]benzopyran-8-carboxylic acid were synthesized and tested for natriuretic and uricosuric activities. Among the compounds tested, 3,5-disubstituted [(4-oxo-4H-1-benzopyran-7-yl)oxy]acetic acids (6c-f, h, n and x) showed potent natriuretic and uricosuric activities, whereas 4-oxo-3-phenyl-4H-furo[2,3-h][1]benzopyran-8-carboxylic acid (6dd) possessed only potent natriuretic activity. The structure-activity relationships are also discussed.

Hylambates-kassinin, a new amphibian skin dodecapeptide of the tachykinin family, was synthesized in a conventional manner using thioanisole-mediated deprotection with trifluoromethanesulfonic acid. The contractile potency of synthetic hylambates-kassinin in isolated guinea-pig duodenum was 1.4 times higher than that of synthetic kassinin.

Human corticotropin releasing factor (hCRF), a hentetracontapeptide amide identical with rat CRF, was synthesized in a conventional manner by assembling nine peptide fragments followed by deprotection with 1 M trifluoromethanesulfonic acid-thioanisole in trifluoroacetic acid.

Hylambatin, a dodecapeptide amide isolated from the skin of an African rhacopharid frog (Hylambates maculatus), was synthesized by two routes, by successive condensations of four fragments, i.e., (1-3), (4-5), (6-10), and (11-12) in one case and (1-3), (4-7), (8-10), and (11-12) in the other, followed by deprotection with 1M trifluoromethanesulfonic acid-thioanisole in trifluoroacetic acid. The S-alkylation observable during Nα-deprotection of Metcontaining peptides with trifluoroacetic acid was found to be suppressed more effectively by the use of 3, 5-dimethylanisole containing 2% ethanedithiol as a scavenger system than by the use of anisole containing 2% ethanedithiol. The contractile potency of synthetic hylambatin in isolated guinea-pig duodenum was 0.42 times that of synthetic kassinin.

Nine peptide fragments were synthesized by known amide-forming reactions as building blocks for the solution synthesis of the hentetracontapeptide amide corresponding to the entire amino acid sequence of human corticotropin releasing factor (hCRF). Amino acid derivatives bearing protecting groups removable by 1M trifluoromethanesulfonic acid-thioanisole in TFA were employed.

A new porcine gastrointestinal 29-residue peptide, galanin, was synthesized in a satisfactory yield by assembling seven peptide fragments followed by deprotection with 1 M trifluoromethane-sulfonic acid-thioanisole in trifluoroacetic acid. Nin-Mesitylenesulfonyltryptophan was employed to suppress indole alkylation during Na-deprotection. β-Cycloheptylaspartate was employed to suppress base-catalyzed succinimide formation. The synthetic peptide exhibited a powerful contractile activity on rat ileum, but not on guinea pig ileum and caused sustained hyperglycemia in dogs.