Design and synthesis of long-acting inhibitors of dipeptidyl peptidase IV

• Published in: Bioorganic & medicinal chemistry 2007-04, Vol.15 (7), p.2715-2735
• Main Authors: Kondo, Takashi, Sugimoto, Isamu, Nekado, Takahiro, Ochi, Kenya, Ohtani, Tazumi, Tajima, Yohei, Yamamoto, Susumu, Kawabata, Kazuhito, Nakai, Hisao, Toda, Masaaki
• Format: Article
• Language: English
• Subjects: Animals; Area Under Curve; Biological and medical sciences; Biological Availability; Chromatography, Thin Layer; Dipeptidyl-Peptidase IV Inhibitors; DPP-IV inhibitor; Drug Design; Drug Stability; General and cellular metabolism. Vitamins; Glucuronate; Glucuronidase - chemistry; Humans; In Vitro Techniques; Indicators and Reagents; Male; Medical sciences; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Pharmacology. Drug treatments; Prolylprolinenitriles; Protease Inhibitors - chemical synthesis; Protease Inhibitors - pharmacokinetics; Protease Inhibitors - pharmacology; Rats; Rats, Sprague-Dawley; Solutions; Spectrometry, Mass, Fast Atom Bombardment; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.01.033

The 4β-[4-(hydroxyphenyl)prolyl]prolinenitriles were synthesized and evaluated as inhibitors of dipeptidylpeptidase IV (DPP-IV). Metabolic formation of the corresponding phenol glucuronates was found to contribute to their long duration of action. A series of (4-substituted prolyl)prolinenitriles were synthesized and evaluated as inhibitors of dipeptidylpeptidase IV (DPP-IV). Among those tested, the 4β-[4-(hydroxyphenyl)prolyl]prolinenitriles showed a potent inhibitory activity with a long duration of action. Metabolic formation of the corresponding phenol glucuronates was found to contribute to their long duration of action. The activity profiles of the synthesized compounds are reported and structure–activity relationships are also presented.