Novel Small Molecule Nonpeptide Aminopeptidase N Inhibitors with a Cyclic Imide Skeleton

Abstract

A novel series of small molecule nonpeptide aminopeptidase N (APN) inhibitors with a N-phenylphthalimide or N-phenylhomophthalimide skeleton were prepared. Evaluation of their protease inhibitory activities revealed that (i) some N-phenylphthalimide analogs are potent APN inhibitors, but they are also inhibitors of another protease, dipeptidylpeptidase IV (DPP-IV), and (ii) some N-phenylhomophthalimide analogs, including 2-(2,6-diethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione (PIQ-22), are potent and specific inhibitors of APN without DPP-IV-inhibitory activity. The structure-activity relationship studies of N-phenylphthalimides and N-phenylhomophthalimides are reviewed. PIQ-22 showed potent tumor-cell invasion-inhibitory activity.

Structural Development of Liver X Receptor (LXR) Antagonists Derived from Thalidomide-Related Glucosidase Inhibitors

“…2). [11][12][13][14][15][16][17][18] CP0P (4) is a non-competitive inhibitor of a-glucosidase, whereas CP4P (5) is a competitive inhibitor. [16][17][18] PPS-33 (6) is another competitive a-glucosidase inhibitor, but it also inhibits other enzymes, including maltase and dipeptidylpeptidase type IV.…”

“…8,9) We have been engaged in structural development studies of thalidomide, a drug first launched as a sedative/hypnotic agent, but withdrawn from the market because of its severe teratogenicity, focusing on its potential for the treatment of a range of diseases, including cancers, diabetes, and rheumatoid arthritis. [11][12][13][14][15] We have developed a series of potent aglucosidase inhibitors, including CP0P (4), CP4P (5) and PPS-33 (6) (Fig. 2).…”

Thalidomide as a Nitric Oxide Synthase Inhibitor and Its Structural Development

“…Although the most effective alkyl substituent could not be deduced from the investigated alkyl groups, the preferred site of substitution seems to be ortho. Quinazolinedione derivatives (12)(13)(14), which are bioisosters of the corresponding homophthalimide derivatives (5-9) in peptidase-inhibitory activity assays, 15) were unexpectedly inactive. Interestingly, reduction of the 3-carbonyl group (substituent Y in Table 1) tivity, while reduction of another carbonyl group at position 1, i.e., compound 18, did not affect the activity.…”

“…Our studies resulted in the creation of TNF-a production regulators (including bi-directional ones, as well as pure inhibitors and enhancers), 3,4,[6][7][8] androgen antagonists, 3,4,9,10) peptidase inhibitors, 4,[11][12][13][14][15] glucosidase inhibitors, 16,17) thymidine phosphorylase inhibitors 18) and cyclooxygenase inhibitors. 19,20) Nevertheless, not all of the beneficial pharmacological effects elicited by thalidomide can be fully interpreted in terms of the above activities, indicating the existence of other target molecules/phenomena.…”

“…So we chose N-phenyl(homo)phthalimide or N-phenylquinazolinedione derivatives as lead compounds, based on our previous studies on peptidase inhibitors and COX inhibitors derived from thalidomide. 4,[12][13][14][15][16]19,20) Substituted phthalimide and homophthalimide compounds were prepared by routine organic synthetic methods, i.e., condensation of appropriate amines with phthalic (3) or homophthalic anhydride (4-11). Quinazolinedione derivatives (12-14) were prepared by the condensation of 2,6-dialkylanilines and methyl anthranilate in the presence of triphosgene.…”