A novel series of second generation DPP1 inhibitors free from aorta binding liabilities found for earlier compound series was discovered. This work culminated in the identification of compound 30 (AZD7986) as a highly potent, reversible, and selective clinical candidate for COPD, with predicted human PK properties suitable for once daily human dosing.

Background and PurposeNeutrophil serine proteases (NSPs) are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. The effects of neutrophil turnover rate on NSP activity following DPP1 inhibition was studied in a rat pharmacokinetic/pharmacodynamic model.Experimental ApproachRats were treated with a DPP1 inhibitor twice daily for up to 14 days; NSP activity was measured in onset or recovery studies, and an indirect response model was fitted to the data to estimate the turnover rate of the response.Key ResultsMaximum NSP inhibition was achieved after 8 days of treatment and a reduction of around 75% NSP activity was achieved at 75% in vitro DPP1 inhibition. Both the rate of inhibition and recovery of NSP activity were consistent with a neutrophil turnover rate of between 4–6 days. Using human neutrophil turnover rate, it is predicted that maximum NSP inhibition following DPP1 inhibition takes around 20 days in human.Conclusions and ImplicationsFollowing inhibition of DPP1 in the rat, the NSP activity was determined by the amount of DPP1 inhibition and the turnover of neutrophils and is thus supportive of the role of neutrophil maturation in the activation of NSPs. Clinical trials to monitor the effect of a DPP1 inhibitor on NSPs should take into account the delay in maximal response on the one hand as well as the potential delay in a return to baseline NSP levels following cessation of treatment.

To evaluate the differential effects of portacaval shunting (PCS) on the morphological changes that occur in humans with portal-systemic encephalopathy, male rats underwent either PCS (13) or sham operations (10). Normal adult rats (6) were used as controls. All animals were killed 5 to 7 weeks after the surgery. The wet weight of the testes was obtained. Hematoxylin-eosin (HE)-stained sections at 5-m thickness were used for stereological analysis using an image analysis system. Apoptosis was assessed quantitatively in HE and in in situ end-labeling (ISEL)-stained slides, while mitotic activity and mast cell numbers were assessed in 20 high-power fields. There was a significant reduction in the testicular mass (664 mg) in PCS rats in comparison with sham (2,199 mg) and control (1,937 mg) rats (P F .00001). The thickness of germinal epithelium was significantly reduced in PCS rats (64 m) compared with sham (126 m) and control groups (108 m). The number of tubules per square millimeter and the mean curvature were significantly increased in PCS rats (P F .00001). There was a 112-fold increase in apoptosis in PCS rats (112) in comparison with the control and shamoperation groups (1.2 and 0.7, respectively). Mitosis was significantly reduced in the PCS group (P ‫؍‬ .0089), but mast cells were unchanged. The results suggest that PCS in the absence of liver dysfunction produces testicular atrophy by reduction in mitosis, maturation arrest, and increased apoptosis of the germinal epithelium. PCS may therefore be responsible for gonadal atrophy that occurs with advanced liver disease in humans. (HEPATOLOGY 1998;28:1461-1466.)The creation of a portacaval shunt (PCS) is often accompanied by hepatic encephalopathy that should be referred to as portal-systemic encephalopathy. The pathogenesis is still obscure, although the condition is probably multifactorial in origin. 1 We 2 and others 3 have studied the physiological and histological changes in the small intestine in this animal model. We found that the decrease in jejunal permeability in the PCS rats was probably related to reduction in mucosal area and villi of the small intestine.It is well known that patients with advanced liver disease show testicular atrophy. The morphological and morphometric changes of testicular atrophy in alcoholic and nonalcoholic liver disease in humans have been described by several authors. 4-8 A rat model for alcohol-induced gonadal atrophy has also been reported. 9 Van Thiel et al. 10 studied the effect of portasystemic shunting and portal hypertension in rats. They found that the weight of the testes was only 42% of the control value in rats with PCS and suggested that portasystemic shunting is principally responsible for the gonadal injury. A small decrease was also observed in rats with portal hypertension from partial portal vein ligation.In this study, we report the changes occurring in the testes in PCS, sham-operated, and normal control rats. We have used a quantitative approach to study the changes in the volume of the testes and i...

The present study show altered but opposite behavior in PCS rats, when challenged with either venlafaxine or citalopram, compared to PCS control rats. These findings therefore support the contention that caution should be advocated when CNS monoamine active drugs are used in liver-impaired subjects until better delineation of the combined pharmacodynamic and pharmacokinetic outcome for each such drug in this condition has been made.

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