| Abstract: | This is the second patent application from Novartis describing N-substituted-2-cyanopyrrolidines as inhibitors of dipeptidyl peptidase IV (DPP-IV). DPP-IV is a serine protease which cleaves Xaa-Pro- or Xaa-Ala- amino terminal sequences from biologically active peptides, transforming them into inactive or even antagonistic species. Among them is glucagon-like peptide 1 (GLP-1), a major stimulator of pancreatic insulin secretion with additional properties in lowering the blood glucose level, which is normally secreted in response to food ingestion. By inhibiting DPP-IV the endogenous GLP-1 is preserved for longer periods, the inhibitors being useful in the treatment of the non-insulin-dependent diabetes mellitus (NIDDM), obesity, arthritis, osteoporosis and other diseases generated or enhanced by impaired glucose tolerance. The compounds claimed in this application are novel N-substituted 2-cyanopyrrolidines bearing adamantyl moieties as biocompatible lipophylic groups; their low nanomolar level of DPP-IV inhibition, as well as their in vivo therapeutic profile, are improved as compared with the results obtained in previous studies. |
