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.

Purpose-The purpose of this paper is to analyse the culture change management programme in one UK NHS ambulance service, documenting various perverse consequences of the change management and suggest further research implications.Design/methodology/approach-The paper reviews the literature on 'culture' and 'culture change' and identifies several perverse consequences of a culture change management programme through an in-depth case study analysis, based on interviews with trust staff and policy experts along with non-participant observation. Study was given ethical approval by the local NHS research ethics committee.Findings-Significant negative consequences of the culture change management programme in the ambulance service are systematically documented. The paper argues that any worthwhile study of organisational culture change management must take into account the perverse consequences of such a process and its overall impact on employees.Research limitations/implications-These findings come from detailed investigation from only one large ambulance trust in the UK. However they have significant implications for the organisational 'culture-performance' debate.Practical implications-The paper draws out several policy and practice implications from this empirical study. Any meaningful evaluation of culture change initiatives should be seen not only in relation to success in achieving planned objectives, but also by keeping in mind negative consequences of culture change programmes.Social implications-The concept of unintended consequences has a long history in organisational theory, but there have been relatively few empirical studies recognising the importance of unintended consequences of cultural management efforts. The impact of cultural change programmes in different organisational settings, including the ambulance service, remains under-researched.Originality/value -This paper makes an original contribution in identifying and systematically documenting the disjuncture between stated and unintended consequences of ambulance culture change management programme, which will be of value to academics, practitioners and policy makers including theory building.

I T has been proposed by Shockley 1 that it may be possible to distinguish experimentally between the vacancy and interstitial diffusion mechanisms by observing mass transfer as the result of a temperature gradient. In particular, it was stated that the temperature gradient should give rise to a diffusion current of defects under steady state conditions and that this current should produce mass transport toward high temperature for vacancies and toward low temperature for interstitial atoms. It is the purpose of the present note to show that this is true only for vacancies in case the formation energy of vacancies, Ef, exceeds the activation energy for their migration, E m , whereas if the reverse is true, the direction of mass flow should be reversed. Thus, the experiments proposed by Shockley may prove of value in determining which energy, E m or Ef, is the larger for materials in which the diffusion mechanism is known to be vacancy migration, rather than in determining whether an interstitial or vacancy migration mechanism is responsible for diffusion.Consider two parallel neighboring planes of atoms perpendicular to the temperature gradient in the material, the first at a temperature T, and the second at T-\-AT, as in Fig. 1. The flow of I o 1 © U --«o T + AT o • --^ © i O i o t_ ENERGY BARRIER, E m FIG. 1. Two neighboring planes of atoms in a crystal, each perpendicular to the temperature gradient.vacancies across a representative pair of atom sites, a and b, will be calculated. In order for a vacancy to flow toward higher temperature via this pair, (1) a must first be vacant and (2) the atom on b must jump the energy barrier, E m , representing the activation energy for vacancy migration. The probability of (1) can be written: Ae~Ef' kT , assuming that the thermal equilibrium concentration is maintained in each plane, and the probability of (2): B e -*E m fk (T+&T) where both the entropy factor, A, and the frequency factor, B, are temperature independent. Thus, the vacancy flow to the right is:ABe~Ef lkT e" Emlk^T+AT) .Similarly, the vacancy flow to the left is:The net flow of vacancies to the right is:, if all terms higher than first order in AT/T are neglected. Thus, the net flow of vacancies is toward higher vacancy concentrations if E m >Ef and toward lower concentrations if E m Ef for face-centered cubic metals, implying that the mass flow should be opposite in direction to that assumed by Shockley.The geometry associated with interstitial migration is more complex, and the conditions under which mass transfer should be toward lower or higher temperatures cannot be calculated easily in an analogous manner.T HE writer is entirely in agreement with the conclusion reached by LeClaire 1 and Brinkman 2 that one of the major mechanisms was unwarrantably disregarded in his first publication. 3 12 3 4FIG. 1. Schematic representation of how the activation energy for jumping is furnished in part by neighbors of a jumping a...

Rhodium and iridium catalysts containing trifluoromethyl-substituted indenyl ligands (Ind'MCod, Ind' = C9H7, (1-CF3)C9H6, (2-CF3)C9H6, (1,3-CF3)2C9H5) have been developed for the directed hydroboration of 4-(benzyloxy)cyclohexene to cis-3-(benzyloxy)cyclohexanol. Compared to unsubstituted complexes, trifluoromethyl substitution yields a 3-10% increase in selectivity which is attributed to the strong electron-withdrawing effect of the trifluoromethyl group. Rhodium complexes give selectivities of 74-84%, and iridium complexes give high levels of selectivity (93-98%).