Synthesis and Biological Evaluations of Novel Human Parathyroid Hormone 1 Receptor (hPTHR1) Agonists Bearing Bicyclic Aromatic Moiety.

We have previously shown that the small molecule hPTHR1 agonist PCO371 (1) orally and dose-dependently induces PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. Compound 2a, bearing a bicyclic aromatic ring, was identified as a novel hPTHR1 agonist during hit to lead modification. It showed moderate PTHR1 agonistic activity with an EC20 value of 15 µM, and its metabolic stability in human liver microsome (hLM) as well as its solubility in phosphate buffer (PPb) and Fasted state simulated intestinal fluid (FaSSIF) were found to be poor. As results of the initial derivatization of 2a, we identified the indole derivatives as another scaffold. In this article, we report on the structure-activity relationship (SAR), structure-metabolism relationship (SMR), and structure-solubility relationship (SSR) of bicyclic aromatic derivatives, and the in vivo efficacy of 2j.

Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist.

We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and orally active PTHR1 agonist 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (PCO371, 16c). This compound is currently being evaluated in a phase 1 clinical study for the treatment of hypoparathyroidism.

Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small Molecule for Treatment of Hypoparathyroidism.

During the course of derivatization of HTS hit 4a, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1 R,4 R)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-1-methylurea (CH5447240, 14l). Compound 14l exhibited a potent in vitro hPTHR1 agonist effect with EC20 of 3.0 µM and EC50 of 12 µM and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, 14l showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats.

Pharmacokinetic disposition of anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in rats and dogs.

The pharmacokinetic disposition of anagliptin, an orally active and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor was evaluated in male rats and dogs. Anagliptin was well absorbed in dogs (70.4 %) and moderately to well absorbed in rats ranging from 38.1 to 85.5 % depending on the dose. In situ testing indicated that anagliptin absorption from rat intestine was apparently limited by P-glycoprotein. The absorbed radioactivity was distributed rapidly throughout the body, and high levels of radioactivity were found in the tissues expressing DPP-4 at high levels, especially small intestine, kidney and liver. In both species, the major circulating component was unchanged anagliptin; major circulating metabolites were M1 resulting from hydrolysis of the cyano group and M6 and M7, both of which resulting from the oxidation-cleavage of the methylene function adjacent to the amine. After intravenous dosing, urinary excretion of radioactivity was the major route of elimination for rats (64.6 %) and dogs (66.2 %), and biliary excretion was demonstrated to be an important pathway in rats (25.2 %). The total recovery was good (97.5-99.5 %) and most of the radioactivity was excreted by 24 h in both species. The renal clearance of unbound anagliptin in rats (91.7 ml/min/kg) was much higher than the glomerular filtration rate, indicative of active renal elimination.

[In-vitro study of the drug interactions between Miglitol, an alpha-glucosidase inhibitor, and adsorbents].

The interactions between miglitol, an alpha-glucosidase inhibitor, and six adsorbents (carbon spheres, cholestyramine, colestimide, sevelamer hydrochloride, calcium polystyrene sulfonate, and sodium polystyrene sulfonate) were investigated in vitro. Miglitol corresponding to the minimum dose and adsorbents corresponding to the maximum dose were incubated at 37 degrees C for 180 min in solutions of pH 1.2 (gastric pH condition) and pH 6.8 (enteric pH condition), with and without the presence of carbohydrates, which were added to observe the effects on food adsorption. The adsorption ratio of miglitol to carbon spheres was 13.6% and 0% in pH 1.2 solution and 86.4% and 5.0% in pH 6.8 solution without and with the presence of carbohydrates, respectively. Thus, the adsorption ratio was higher in pH 6.8 solution. Adsorption of miglitol to calcium polystyrene sulfonate was nearly the same, 15.0-21.9%, at both pH. The adsorption ratio of miglitol to sodium polystyrene sulfonate was 43.4% and 45.5%, respectively, in pH 1.2 solution without and with carbohydrates. In the pH 6.8 solutions, however, the respective adsorption ratios were low (5.2% and 11.3%). Miglitol did not adsorb to cholestyramine, sevelamer hydrochloride or colestimide under any pH condition examined. The above results suggest that miglitol adsorbs to carbon spheres and polystyrene sulfonic acid cation exchange resins. However, considering that miglitol is taken just before eating and thus exists in gastointestinal fluids together with food, and that the site of its effect is the upper small intestine, the interactions between miglitol and these adsorbents will most likely not be a problem.

Discovery of 7alpha-substituted dihydrotestosterones as androgen receptor pure antagonists and their structure-activity relationships.

A series of 7alpha-substituted dihydrotestosterone derivatives were synthesized and evaluated for androgen receptor (AR) pure antagonistic activity. From reporter gene assay (RGA), the compound with a side chain containing N-n-butyl-N-methyl amide (19a) showed pure antagonistic activity (IC(50)=340nM, FI(5)>10,000nM), whereas known AR antagonists showed partial agonistic activities. The optimization of 19a led to compound 23 (CH4892280), which showed more potent pure antagonistic activity (IC(50)=190nM, FI(5)>10,000nM). The SARs of tested compounds suggested that the length of the side chain and the substituents on the amide nitrogen are important for pure antagonistic activities.

Design and evaluation of new antipsoriatic antedrug candidates having 16-en-22-oxa-vitamin D3 structures.

Design, synthesis, and in vitro and in vivo evaluation of a series of antipsoriatic antedrugs having 16-en-22-oxa-vitamin D3 are described. Among the seven compounds examined, two are promising: ester 5c and amide 5f, both of which exhibit greater potent antiproliferation activity with lessened calcemic activity than the presently prescribed maxacalcitol (2).

Pharmacokinetic and pharmacodynamic studies of SK-896, a new human motilin analogue, in healthy male volunteers.

OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of SK-896 ([Leu(13)]motilin-Hse) after intravenous administration to healthy male volunteers. DESIGN AND SETTING: This was a non-blinded phase I study. PARTICIPANTS: Thirty male Japanese volunteers (mean age 30.6 years) participated in this study. The volunteers were divided into five groups receiving different doses of SK-896. METHODS: The pharmacokinetics and pharmacodynamics of SK-896 were evaluated after single intravenous infusions of doses of 10, 20, 40 and 80 micro g over 20 minutes to fasting volunteers, or after multiple intravenous infusions (twice a day for 3 days) of doses of 40 micro g over 20 minutes to volunteers in the morning (fasting) and afternoon (non-fasting). Plasma concentrations of immunoreactive SK-896 were determined by radioimmunoassay, and borborygmus was measured as an indicator of drug effect (acceleration of gastrointestinal motility) with an improved Holter electrocardiograph attached to the abdomen. RESULTS: When SK-896 was given by single intravenous infusion at each dose, the plasma concentration of immunoreactive SK-896 rapidly increased to a maximum at the end of the infusion. After the infusion was completed, plasma concentrations declined monoexponentially with an elimination half-time of 4.57-5.64 minutes. The area under the concentration-time curve and the maximum concentration (1.04-9.08 microg-equiv./L) increased in proportion to the dose, and there were no dose-related changes in plasma clearance (7.59-9.34 mL/min/kg), mean residence time (7.83-9.51 minutes) or steady-state volume of distribution (62.9-73.9 mL/kg), indicating that SK-896 plasma concentrations can be described by a linear pharmacokinetic model within the dose range of the present study. After beginning administration, an increase in borborygmus was observed. At doses of 40 and 80 micro g, the borborygmus did not continue even when the plasma concentration was maintained, suggesting that tachyphylaxis occurs at a higher dose. When SK-896 was given as multiple intravenous infusions, the pharmacokinetics did not change with repeated administration. The intensity of borborygmus was low with afternoon administration, reaching only one-third to one-half that with morning administration, suggesting that, like native motilin, SK-896 does not stimulate gastrointestinal motility in the non-fasting state. CONCLUSIONS: The appropriate dose and administration period (fasting or non-fasting) are important factors in stimulating and maintaining gastrointestinal motility when treating gastroparalysis with SK-896.

Effects of SK-896, a new human motilin analogue ([Leu13]motilin-Hse), on postoperative ileus in dogs after laparotomy.

The effects of SK-896, a new human motilin analogue ([Leu13]motilin-Hse), on digestive tract motility in postoperative ileus were evaluated in a dog model of ileus after laparotomy. SK-896 was intravenously administered at 0.17, 0.33 and 0.67 microg/kg starting soon after operation and then at 6-h intervals, for a total of 9 times. SK-896 progressively, dose-dependently and significantly increased the duodenal motility from 1 h after operation. The recovery time of the gastrointestinal-interdigestive migrating complex (GI-IMC) activity, which is an indicator of normal gastrointestinal tract activity after laparotomy, was 56.5 +/- 5.0 h in the control group. SK-896 significantly shortened this recovery time. On the other hand, the plasma SK-896 concentrations declined diexponentially after administration, and can be described by a linear pharmacokinetic model within the dose range used. In addition, the pharmacokinetics of SK-896 did not change significantly at any postoperative time. There was no correlation between the plasma SK-896 concentrations and the intensity of duodenal motility, because the activity in the duodenum decreased transiently 13 h after laparotomy and increased with time thereafter. The changes in the activity are considered to reflect the progressive changes in the state of ileus. In conclusion, SK-896 increased the duodenal motility significantly, shortening the recovery time of GI-IMC-like activity in dogs with post-laparotomy ileus. Therefore, it is expected from these results that SK-896 would be useful and effective for the treatment of gastroparalysis after abdominal surgery.