Aim: To further characterize the properties of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB), a recently described novel and potent inhibitor of glycogen phosphorylase and potential anti-diabetic agent, we have determined its pharmacokinetic properties in rats, dogs and mice and compared these to its pharmacodynamic anti-hyperglycaemic efficacy.Methods: Male Sprague Dawley rats, beagle dogs and diabetic Umea ob/ob mice were administered DAB or C-14-DAB at various doses and by different routes and in either the conscious or the unconscious state and with or without glucagon, as appropriate. At different time points thereafter, blood, tissue and urine samples were withdrawn for analyses of DAB or C-14-DAB, and blood samples were taken for glucose concentration.Results: DAB suppressed the blood glucose excursion in glucagon-challenged rats with an ID100 of 1-2 mg/kg per orally and intravenously and had a pharmacodynamic t(50) for 1.6 mg/kg intravenously and for 1.2 mg/kg per orally of 50 and 60 min respectively. The pharmacokinetics of c. 2 mg/kg DAB in rats revealed elimination half-lives of 25 min after intravenous (i.v.) and 49 min after per oral (p.o.) administration; the oral bioavailability was 89%. In rats, DAB was distributed preferentially in liver vs. skeletal muscle and was eliminated predominantly through urine as parent compound. The pharmacokinetics of 4 mg/kg DAB in dogs showed elimination half-lives of 107 min after i.v. and 129 min after p.o. administration with an estimated oral availability of 78%. At 4 mg/kg DAB p.o., glucagon-induced hyperglycaemia in dogs was reduced in a time-dependent manner with an estimated t(50) of 4 h. DAB was very rapidly cleared in mice; nevertheless, a dose-dependent reduction of blood glucose of up to 9 mmol/l was seen in diabetic ob/ob mice dosed subcutaneously, with statistically significant effects evident from 30 to 120 min.Conclusions: These data show that DAB is nearly completely orally available in rats and dogs and that it can reduce glucagon-induced and spontaneous hyperglycaemia. Inhibition of hepatic glycogen phosphorylase may benefit glycaemic control in patients with type 2 diabetes.

Two potent nonselective, but PPARalpha-preferring, PPAR agonists 5 and 6 were designed and synthesized in high yields. The concept of dimeric ligands in transcription factors was investigated by synthesizing and testing the corresponding dimers 7, 8a, and 8b in PPAR transactivation assays. The three dimeric ligands all showed agonist activity on all three PPAR receptor subtypes, but with different profiles compared to the monomers 5 and 6. Despite breaking all the "rule of five" criteria, the dimers had excellent oral bioavailability and pharmacokinetic properties, resulting in good in vivo efficacy in db/db mice. X-ray crystal structure and modeling experiments suggested that the dimers interacted with the AF-2 helix as well as with amino acid residues in the lipophilic pocket close to the receptor surface.

Highly potent human glucagon receptor (hGluR) antagonists have been prepared employing both medicinal chemistry and targeted libraries based on modification of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well as the (distal) benzylic aryl group of the lead 2, 3-eyano-4-hydroxybenzoic acid (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles were found to be active. The SAR was found to be quite insensitive regarding the linkage to the distal aryl group, since long and short as well as polar and apolar linkers gave highly potent compounds. The presence of a distal aryl group was not crucial for obtaining high binding affinity to the hGluR. In many cases, however, the affinity could be further optimized with substituted distal aryl groups. Representative compounds have been tested for in vitro metabolism, and structure-metabolism relationships are described. These efforts lead to the discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylenelhydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC50 = 2.3 nM, K-B = 760 pM) and of the isolated rat receptor IC50 = 430 pM, K-B = 380 pM). Glucagon-stimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (K-i = 14 nM). This compound was orally available in dogs (F-po = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.

Synthesis and structure-activity relationships of tricyclic alpha-ethoxy-phenylpropionic acid derivatives guided by in vitro PPARalpha and PPARgamma transactivation data and computer modeling led to the identification of the novel carbazole analogue, 3q, with dual PPARalpha (EC50 = 0.36 muM) and PPARgamma (EC50 = 0.17 muM) activity in vitro. Ten days treatment of db/db mice with 3q improved the insulin sensitivity, as measured by OGTT, better than that seen with both pioglitazone and rosiglitazone treatment, suggesting in vivo PPARgamma activity. Likewise, 3q lowered plasma triglycerides and cholesterol in high cholesterol fed rats after 4 days treatment, indicating in vivo PPARalpha activity. Investigations of the pharmacokinetics of selected compounds suggested that extended drug exposure improved the in vivo activity of in vitro active compounds.

6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives were synthesized and characterized as activators of adenosine 5'-triphosphate (ATP) sensitive potassium (K(ATP)) channels in the beta-cells by measuring effects on membrane potential and insulin release in vitro. The effects on vascular tissue in vitro were measured on rat aorta and small mesenteric vessels. Selected compounds were characterized as competitive inhibitors of [(3)H]glibenclamide binding to membranes of HEK293 cells expressing human SUR1/Kir6.2 and as potent inhibitors of insulin release in isolated rat islets. 6-Chloro-3-(1-methylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (54) was found to bind and activate the SUR1/Kir6.2 K(ATP) channels in the low nanomolar range and to be at least 1000 times more potent than the reference compound diazoxide with respect to inhibition of insulin release from rat islets. Several compounds, e.g., 3-propylamino- (30), 3-isopropylamino- (34), 3-(S)-sec-butylamino- (37), and 3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (53), which were found to be potent and beta-cell selective activators of K(ATP) channels in vitro, were found to inhibit insulin secretion in rats with minimal effects on blood pressure and to exhibit good oral pharmacokinetic properties.

The aim of the present study was to assess the safety, pharmacokinetics and pharmacodynamics (including specificity) of NN703 (tabimorelin), a growth hormone (GH) secretagogue, in healthy male subjects following treatment for 7 days once-daily. This was a randomized, double-blind and placebo-controlled study with four active dose levels: 1.71, 3.0, 4.5 and 6.86 mg/kg body weight. There was a dose-related increase for GH area under the curve (AUC) (0-12 h) and GH C(max)(0--12 h); these were significantly higher on both days 1 and 7 as compared with placebo treatment (P = 0.04 to P< 0.0001); however, an overall significant decrease in GH release was found from day 1 to day 7 (P< 0.001). Insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) increased at all dose levels (including placebo); however, a significantly higher increase as compared with placebo treatment was observed at the three highest dose levels for IGF-I (P = 0.04--0.0006) and at the highest dose level for IGFBP-3 (P = 0.03). There was no statistically significant increase in AUC (0-5 h) for follicle-stimulating hormone, luteinizing hormone and cortisol between active and placebo treatment for day 1 or 7. On day 1 only, a statistically significant increase in AUC (0--5 h) was found for prolactin at 1.71 and 6.86 mg/kg (P< 0.05), for thyroid-stimulating hormone (TSH) at 3.0 mg/kg (P< 0.01) and for adrenocorticotrophic hormone (ACTH) at 4.5 mg/kg (P< 0.05); however, no dose--response relationship was observed for TSH or ACTH. In addition, a statistically significant decrease in AUC (0--5 h) for ACTH (3.0 and 6.86 mg/kg) and cortisol (1.71 mg/kg) was observed on day 7 (P< 0.05). Thus, NN703 is a promising candidate for treatment of absolute or relative GH deficiency.

The objective of this study was to describe the pharmacokinetics and pharmacodynamics of NN703, a growth hormone (GH)-releasing secretagogue, after po administration to healthy human male subjects. The study was designed as a randomized, placebo-controlled, double-blind, dose-escalating, single-dose trial of NN703 covering eight dose levels. Each of the dose levels had 6 subjects on active treatment and 2 subjects on placebo. NN703 was administered po as a solution. Blood samples for serum concentrations of NN703 and GH were collected before dosing and up to 24 hours after dosing. Serum concentrations of NN703 were determined using a validated analytical method, based on solid-phase extraction and LC/MS/MS detection. A two-compartmental model with zero-order input was used to describe the pharmacokinetics of NN703. The parameters of the elimination phase were fitted simultaneously, whereas the parameters describing the absorption phase were allowed to vary between the dose levels. The pharmacodynamics of NN703 was described by use of an indirect-response model containing both a threshold value and a modulator for the development of tolerance. It was concluded that the absorption of NN703 after po administration was nonlinear; the bioavailability increased with the dose. The serum concentration of NN703 required for half-maximal stimulation of GH was determined to be 485 ng/ml. The proposed indirect-response model requiring a threshold concentration and development of tolerance provided a useful mean of quantifying the effects of NN703. Furthermore, the development of tolerance shown based on pharmacokinetic/pharmacodynamic modeling of single-dose data presented here has been confirmed following multiple dosing in healthy male subjects.

The aim of the present study was to investigate the pharmacodynamics, pharmacokinetics, safety and tolerability of a single dose of NN703 (tabimorelin), a growth hormone secretagogue in healthy male subjects. The study design was double blind, randomized and placebo-controlled, with eight escalating dose levels (0.05-12 mg/kg bodyweight (BW)). NN703 was well tolerated by the subjects. The GH area under the curve (AUC) (0-24 h) was significantly higher when compared to placebo for the three highest dose levels (3.0 mg/kg: P = 0.027, 6.0 mg/kg: P = 0.0023, 12 mg/kg: P< 0.0001), and for GH maximal concentration C(max)the four highest dose levels were also significantly higher when compared to placebo (1.5 mg/kg: P = 0.04, 3.0 mg/kg: P = 0.0143, 6.0 mg/kg: P = 0.0053, 12 mg/kg: P = 0.0007). Furthermore, there was a significant increase in IGF-1 levels when compared to placebo for the 6.0 and 12.0 mg/kg BW dose levels (P< 0. 0001). Statistical analysis comparing the AUC (0-24 h) of the NN703 (four highest dose levels) and placebo-treated groups showed no significant increases following NN703 for ACTH, LH, FSH, TSH, prolactin, and cortisol, however, subtle individual changes were noted in ACTH, cortisol and prolactin at doses above 3.0 mg/kg. In conclusion, NN703 is a promising potential candidate for treatment of GH deficiency/insufficiency.

NNC 756 is a new benzazepine with high affinity and selectivity for D1-dopamine receptors. In a double-blind, placebo controlled, cross-over study, positron emission tomography and the radioligand [11C]SCH 23390 were used to determine central D1-do-pamine receptor occupancy after a single oral dose of 80 mg NNC 756 in three healthy men. NNC 756 induced 75, 66 and 47% occupancy of D1-dopamine receptors in the putamen of at 1.5 h after drug administration and 46, 36 and 24% after 7.5 h. There was a hyperbolic relationship between the occupancy values and the serum concentrations. The Ki value for the hyperbola was 6.4 ng/ml (±SD 1.4). The occupancy at 1.5 h is on the same level as that shown to induce effects in animal models for prediction of antipsychotic effect. Restlessness (akathisia) appeared in two subjects and nausea in one subject at time of peak drug concentration in serum. The oral dose level of 80 mg should be appropriate to investigate the potential antipsychotic effect of NNC 756.