A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.

Dipeptidyl peptidase (DPP)-IV inhibitors are a new approach to the treatment of type 2 diabetes. DPP-IV is a member of a family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; DPP-IV is a key regulator of incretin hormones, but the functions of other family members are unknown. To determine the importance of selective DPP-IV inhibition for the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies and in acute dog tolerability studies. In rats, the DPP8/9 inhibitor produced alopecia, thrombocytopenia, reticulocytopenia, enlarged spleen, multiorgan histopathological changes, and mortality. In dogs, the DPP8/9 inhibitor produced gastrointestinal toxicity. The QPP inhibitor produced reticulocytopenia in rats only, and no toxicities were noted in either species for the selective DPP-IV inhibitor. The DPP8/9 inhibitor was also shown to attenuate T-cell activation in human in vitro models; a selective DPP-IV inhibitor was inactive in these assays. Moreover, we found DPP-IV inhibitors that were previously reported to be active in models of immune function to be more potent inhibitors of DPP8/9. These results suggest that assessment of selectivity of potential clinical candidates may be important to an optimal safety profile for this new class of antihyperglycemic agents. Diabetes

The timing and relative intensity of electromyographic activity of hip abductor and extensor muscles were recorded during free and fast velocity walking and during ascent and descent of stairs. Eleven healthy subjects were tested using fine wire electrodes to record the electromyographic activity. Data were quantified by normalizing all electromyographic activity during gait with electromyographic activity occurring during a sustained maximum isometric effort resisted either manually or with a dynamometer. The results indicated that the hip extensor muscles had different phasic patterns and moments of peak activity. During level walking, the semimembranosus and long head of the biceps femoris muscles displayed the greatest swing phase activity (beginning in mid-swing). The adductor magnus muscle followed with its onset in terminal swing. Both this muscle and the gluteus maximus were the principal hip extensors active during the loading response. For ascending stairs, the lower portion of the gluteus maximus muscle proved to be the main hip extensor during the loading response and mid-stance. The findings also showed that the upper portion of the gluteus maximus muscle functioned more like the gluteus medius muscle than the lower portion of the gluteus maximus muscle during both level and stair walking.

Decoding facial expressions of emotion is an important aspect of social communication that is often impaired following psychiatric or neurological illness. However, little is known of the cognitive components involved in perceiving emotional expressions. Three dual task studies explored the role of verbal working memory in decoding emotions. Concurrent working memory load substantially interfered with choosing which emotional label described a facial expression (Experiment 1). A key factor in the magnitude of interference was the number of emotion labels from which to choose (Experiment 2). In contrast the ability to decide that two faces represented the same emotion in a discrimination task was relatively unaffected by concurrent working memory load (Experiment 3). Different methods of assessing emotion perception make substantially different demands on working memory. Implications for clinical disorders which affect both working memory and emotion perception are considered.

Voltage-gated calcium channel (Ca v )2.2 (N-type calcium channels) are key components in nociceptive transmission pathways. Ziconotide, a state-independent peptide inhibitor of Ca v 2.2 channels, is efficacious in treating refractory pain but exhibits a narrow therapeutic window and must be administered intrathecally. We have discovered an N-triazole oxindole, (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1), as a small-molecule, state-dependent blocker of Ca v 2 channels, and we investigated the therapeutic advantages of this compound for analgesia. TROX-1 preferentially inhibited potassium-triggered calcium influx through recombinant Ca v 2.2 channels under depolarized conditions (IC 50 ϭ 0.27 M) compared with hyperpolarized conditions (IC 50 Ͼ 20 M). In rat dorsal root ganglion (DRG) neurons, TROX-1 inhibited -conotoxin GVIA-sensitive calcium currents (Ca v 2.2 channel currents), with greater potency under depolarized conditions (IC 50 ϭ 0.4 M) than under hyperpolarized conditions (IC 50 ϭ 2.6 M), indicating state-dependent Ca v 2.2 channel block of native as well as recombinant channels. TROX-1 fully blocked calcium influx mediated by a mixture of Ca v 2 channels in calcium imaging experiments in rat DRG neurons, indicating additional block of all Ca v 2 family channels. TROX-1 reversed inflammatory-induced hyperalgesia with maximal effects equivalent to nonsteroidal anti-inflammatory drugs, and it reversed nerve injury-induced allodynia to the same extent as pregabalin and duloxetine. In contrast, no significant reversal of hyperalgesia was observed in Ca v 2.2 gene-deleted mice. Mild impairment of motor function in the Rotarod test and cardiovascular functions were observed at 20-to 40-fold higher plasma concentrations than required for analgesic activities. TROX-1 demonstrates that an orally available state-dependent Ca v 2 channel blocker may achieve a therapeutic window suitable for the treatment of chronic pain.Inflammatory diseases and neuropathic insults are frequently accompanied by severe debilitating pain, which can become chronic and unresponsive to conventional analgesic treatments. Intrathecal administration of conventional agents, including morphine, may be required in more severe C.A. and O.B.M. contributed equally to this work. Article, publication date, and citation information can be found at