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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.