Structure−Activity Relationship of Diaryl Phosphonate Esters as Potent Irreversible Dipeptidyl Peptidase IV Inhibitors

• Published in: Journal of medicinal chemistry Vol. 42; no. 6; pp. 1041 - 1052
• Main Authors: Belyaev, Alexander, Zhang, Xuemei, Augustyns, Koen, Lambeir, Anne-Marie, De Meester, Ingrid, Vedernikova, Irina, Scharpé, Simon, Haemers, Achiel
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.03.1999; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Chemistry, Medicinal; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - antagonists & inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - blood; Drug Stability; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Humans; Immunomodulators; In Vitro Techniques; Kinetics; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - enzymology; Life Sciences & Biomedicine; Male; Medical sciences; Mice; Organophosphonates - chemical synthesis; Organophosphonates - chemistry; Organophosphonates - metabolism; Organophosphonates - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Proline - analogs & derivatives; Proline - chemical synthesis; Proline - chemistry; Proline - metabolism; Proline - pharmacology; Rabbits; Rats; Rats, Wistar; Science & Technology; Structure-Activity Relationship; ACTIVATION; STABLE INHIBITORS; CD26; PROLIFERATION; SUPPRESSION; AMINOPEPTIDASE-IV; Rat; Nitrogen heterocycle; Rabbit; Phosphorus Organic compounds; Pyrrolidine derivatives; Mononuclear cell; Structure activity relation; Hydrochlorides; Chemical synthesis; Dipeptidyl-peptidase IV; Human; Stability; Enzyme; Rodentia; Enzyme inhibitor; Organic phosphonate; Lagomorpha; In vitro; Immunomodulator; Peptidases; In vivo; Hydrolysis resistance; Vertebrata; Mammalia; Animal; Hydrolases; Carboxamide
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm981033g

The previously reported diphenyl 1-(S)-prolylpyrrolidine-2(R,S)-phosphonate (5) was used as a lead compound for the development of potent and irreversible inhibitors of dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5). The synthesis of a series of diaryl 1-(S)-prolylpyrrolidine-2(R,S)-phosphonates with different substituents on the aryl rings (hydroxyl, methoxy, acylamino, sulfonylamino, ureyl, methoxycarbonyl, and alkylaminocarbonyl) started from the corresponding phosphites. A good correlation was found between the electronic properties of the substituent and the inhibitory activity and stability. The most striking divergence of this correlation was the high potency combined with a high stability of the 4-acetylamino-substituted derivative 11e. This compound shows low cytotoxicity in human peripheral blood mononuclear cells and also has favorable properties in vivo. Therefore bis(4-acetamidophenyl) 1-(S)-prolylpyrrolidine-2(R,S)-phosphonate (11e) is considered as a major improvement and will be a highly valuable DPP IV inhibitor for further studies on the biological function of the enzyme and the therapeutic value of its inhibition.