Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. The synthesis and structure-activity relationship of a new DPP-IV inhibitor class, N-substituted-glycyl-2-cyanopyrrolidines, are described as well as the path that led from clinical development compound 1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728, 8c) to its follow-up, 1-[[(3-hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP-LAF237, 12j). The pharmacological profile of 12j in obese Zucker fa/fa rats along with pharmacokinetic profile comparison of 8c and 12j in normal cynomolgus monkeys is discussed. The results suggest that 12j is a potent, stable, selective DPP-IV inhibitor possessing excellent oral bioavailability and potent antihyperglycemic activity with potential for once-a-day administration.

The nature of the permanent damage retained in metals from irradiation has been investigated in somewhat greater detail than has been done in the past. The usual assumption has been that the damage in all metals consists chiefly of interstitial-vacancy pairs. The model presented in this paper reduces to this picture for the light elements but introduces a new concept in the case of damage in the heavy metals, called a displacement spike. Calculations are made from which one can estimate the relationship between the density of interstitial-vacancy pairs and the temperature of the associated thermal spike. An assumption regarding the extent to which interstitial-vacancy pairs persist throughout the duration of the thermal spike has been made, based upon these calculations. The number of interstitial-vacancy pairs predicted in the heavy elements is considerably smaller than that predicted by the former model. A mechanism is proposed by which small dislocation loops can be produced in the heavier metals by irradiation. This article is based upon studies conducted for the U. S. Atomic Energy Commission under Contract AT-11–1-GEN-8.

Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. We report the first use of solid-phase synthesis in the discovery of a new DPP-IV inhibitor class and a solution-phase synthesis that is practical up to the multikilogram scale. One compound, NVP-DPP728 (2), is profiled as a potent, selective, and short-acting DPP-IV inhibitor that has excellent oral bioavailability and potent antihyperglycemic activity.

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The processes by which atoms in solids are displaced from their normal positions by high-energy neutrons, cyclotron particles, and electrons are discussed. A radiation damage model is presented which involves two basic features: (1) the production of interstitial atoms and vacant lattice sites, and (2) the production of displacement spikes. These two concepts are sufficient to account for most of the observed property changes resulting from atomic displacement by high-energy particles. Some of the experimental results which provide the most direct support for these concepts are presented.