Discovery of fevipiprant (NVP-QAW039), a potent and selective DP2 receptor antagonist for treatment of asthma

Further optimization of an initial DP2 receptor antagonist clinical candidate NVPQAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2- (trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma

Application of a deuterium replacement strategy to modulate the pharmacokinetics of NVS-CRF38, a novel CRF1 antagonist

Deuterium isotope effects were evaluated as a strategy to optimize the pharmacokinetics of NVS-CRF38, a novel CRF1 receptor antagonist. In an attempt to supress O-demethylation of NVS-CRF38 without losing activity against the CRF1 receptor, the protons at the site of metabolism were replaced with deuterium. For in vitro and in vivo studies intrinsic primary isotope effects (KH/KD) were determined by the ratio of CLint obtained from the nondeuterated and deuterated substrate. In vitro isotope effects were more pronounced when CLint values were calculated based on the rate of formation of the O-desmethyl metabolite (KH/KD ~7), compared to the substrate depletion method (KH/KD ~2). In vivo isotope effects were measured in the rat after intravenous (1 mg/kg) and oral (10 mg/kg) administration. For both administration routes isotope effects calculated from in vivo CLint corresponding to all biotransformation pathways were lower (KH/KD ~2) compared to CLint values calculated from the O-demethylation reaction alone (KH/KD ~7). Comparative metabolite identification studies were undertaken using rat and human microsomes to explore the potential for metabolic switching. As expected a marked reduction of the O-demethylated metabolite was observed for the nondeuterated substrate, however levels of NVS-CRF38’s other metabolites increased, compensating to some extent for the isotope effect

1-aminobenzotriazole modulates oral drug pharmacokinetics through cytochrome P450 inhibition and delay of gastric emptying in rats

The simultaneous effect of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) on inhibition of in vivo metabolism and gastric emptying was evaluated with the test compound NVS308, a novel CRF1 antagonist with low water solubility, and the reference compound midazolam with high water solubility in rats. Pre-treatment of rats with 100 mg/kg oral. ABT administered 2 hours prior to a semi-solid caloric test meal, markedly delayed gastric emptying. ABT increased stomach weights by 2-fold, this is likely to be attributed to a pro-secretory effect because stomach concentrations of bilirubin were comparable in ABT and control groups. ABT administration decreased the initial systemic exposure of orally administered NVS308 and increased Tmax 40-fold, suggesting gastric retention and delayed oral absorption. ABT increased the initial systemic exposure of midazolam, however for orally (but not subcutaneously) administered midazolam, extensive variability in plasma-concentration time profiles was apparent. Careful selection of administration routes is recommended for ABT use in vivo, variable oral absorption of co-administered compounds can be expected due to a disturbance of gastrointestinal transit

Prediction of drug clearance by glucuronidation from in vitro data: Use of combined cytochrome P450 and UDP-glucuronosyltransferase cofactors in alamethicin-activated human liver microsomes

Glucuronidation via UDP-glucuronosyltransferase (UGT) is an increasingly important clearance pathway. In this study intrinsic clearance (CL(int)) values for buprenorphine, carvedilol, codeine, diclofenac, gemfibrozil, ketoprofen, midazolam, naloxone, raloxifene, and zidovudine were determined in pooled human liver microsomes using the substrate depletion approach. The in vitro clearance data indicated a varying contribution of glucuronidation to the clearance of the compounds studied, ranging from 6 to 79% for midazolam and gemfibrozil, respectively. The CL(int) was obtained using either individual or combined cofactors for cytochrome P450 (P450) and UGT enzymes with alamethicin activation and in the presence and absence of 2% bovine serum albumin (BSA). In the presence of combined P450 and UGT cofactors, CL(int) ranged from 2.8 to 688 microl/min/mg for zidovudine and buprenorphine, respectively; the clearance was approximately equal to the sum of the CL(int) values obtained in the presence of individual cofactors. The unbound intrinsic clearance (CL(int, u)) was scaled to provide an in vivo predicted CL(int); the data obtained in the presence of combined cofactors resulted in 5-fold underprediction on average. Addition of 2% BSA to the incubation with both P450 and UGT cofactors reduced the bias in the clearance prediction, with 8 of 10 compounds predicted within 2-fold of in vivo values with the exception of raloxifene and gemfibrozil. The current study indicates the applicability of combined cofactor conditions in the assessment of clearance for compounds with a differential contribution of P450 and UGT enzymes to their elimination. In addition, improved predictability of microsomal data is observed in the presence of BSA, in particular for UGT2B7 substrates

Preclinical metabolism and pharmacokinetics of NVS-CRF38, a potent and orally bioavailable corticotrophin-releasing factor-1 antagonist

1. The pharmacokinetic properties and metabolism of NVS-CRF38 [7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole] were determined in vitro and in animals. 2. NVS-CRF38 undergoes near complete absorption in rats and dogs. In both species the compound has low hepatic extraction and is extensively distributed to tissues. 3. In hepatic microsomes and cryopreserved hepatocytes NVS-CRF38 was metabolised to form O-desmethyl NVS-CRF38 (M7) and several oxygen adducts (M1, M3, M4, M5, and M6). In hepatocytes further metabolites were observed, specifically the carboxylic acid (M2) and conjugates (sulphate and glucuronide) of M7. 4. Formation of primary metabolites in hepatocytes was blocked by the cytochrome P450 suicide inhibitor 1-aminobenzotriazole, implicating cytochrome P450 enzymes in the primary metabolism of this compound. 5. NVS-CRF38 is weakly bound to blood from rat (fub = 0.19), dog (fub = 0.25), monkey (fub = 0.20) and humans (fub = 0.23). Blood-to-plasma partition for NVS-CRF38 approaches unity in rats and human blood. 6. The hepatic clearance of NVS-CRF38 in humans is predicted to be low (extraction ratio ~ 0.2) based on scaling from drug depletion profiles in hepatic microsomes

Do We Need to Study Metabolism and Distribution in the Eye: Why, When, and Are We There Yet?

The liver is known to be the principal site of drug metabolism. Depending on the route of administration, especially in cases of topical and local delivery, evaluation of local drug metabolism in extrahepatic tissues is vital to assess fraction of the drug metabolized. This parameter becomes important from the point of view of drug availability or the contribution to overall clearance. Examples include fraction metabolized in the gut for oral drugs and contribution of pulmonary or renal clearance to total clearance of a drug. Diseases of the eye represent a rising unmet medical need and a number of therapeutics are currently being developed in the form of small molecules and biologics. Treatment of ocular diseases has expanded to explore various topical formulations and local short- and long-term therapies by ocular routes of administration. Until recently, metabolism in the eye for any species, including human, was not well documented, but this topic is gaining wide interest. Many in vitro-ex vivo models, each with separate pros and cons, are being used for studying ocular metabolism. This review is aimed at providing a perspective on the relevance and application of ocular metabolism, melanin binding, and the use of tissue- and cell-derived ocular models in discovery and preclinical development

Discriminative stimulus effects of tiagabine and related GABAergic drugs in rats.

RATIONALE: Tiagabine is an anticonvulsant drug which may also have sleep-enhancing properties. It acts by inhibiting reuptake at the gamma-aminobutyric acid (GABA) transporter (GAT-1). OBJECTIVES: The aim of the study was to determine whether tiagabine acted as a discriminative stimulus and, if so, whether other GABAergic compounds would generalise to it. MATERIALS AND METHODS: Rats were trained to discriminate tiagabine (30 mg/kg p.o.) from vehicle, and generalisation to drugs that modulate GABA was assessed. RESULTS: Gaboxadol (5-20 mg/kg p.o.), a selective extrasynaptic GABA A agonist, generalised to tiagabine, although the extent of the generalisation was inconclusive. Indiplon (1 mg/kg p.o.), a benzodiazepine-like hypnotic, also partially generalised to tiagabine, although zolpidem and S-zopiclone did not. Baclofen, a GABA B receptor agonist, and gabapentin, which increases synaptic GABA, did not generalise to tiagabine. (+)-Bicuculline (3 mg/kg i.p.), a GABA A receptor antagonist, blocked the tiagabine cue, but the less brain-penetrant salt form, bicuculline methochloride, had no effect. CONCLUSIONS: These data suggest that tiagabine generates a discriminative stimulus in rats, and provides a central GABA-mediated cue, but is distinct from the other GABAergic compounds tested

Title Page 1-aminobenzotriazole modulates oral drug pharmacokinetics through cytochrome P450 inhibition and delay of gastric emptying in rats

Non-standard abbreviations: ABT, 1-aminobenzotriazole; AUC, area under the concentration-time curve; C max , Highest drug concentration observed in plasma after administration of extravascular dose; P450, cytochrome P450; LC-MS/MS, liquid chromatography tandem mass spectrometry; T max , Time at which highest concentration occurs after extravascular dose. DMD#056408 3 Abstract The simultaneous effect of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) on inhibition of in vivo metabolism and gastric emptying was evaluated with the test compound NVS-CRF38, a novel CRF 1 antagonist with low water solubility, and the reference compound midazolam with high water solubility in rats. Pre-treatment of rats with 100 mg/kg oral ABT administered 2 hours prior to a semi-solid caloric test meal, markedly delayed gastric emptying. ABT increased stomach weights by 2-fold, this is likely to be attributed to a prosecretory effect because stomach concentrations of bilirubin were comparable in ABT and control groups. ABT administration decreased the initial systemic exposure of orally administered NVS-CRF38 and increased T max 40-fold, suggesting gastric retention and delayed oral absorption. ABT increased the initial systemic exposure of midazolam, however for orally (but not subcutaneously) administered midazolam, extensive variability in plasmaconcentration time profiles was apparent. Careful selection of administration routes is recommended for ABT use in vivo, variable oral absorption of co-administered compounds can be expected due to a disturbance of gastrointestinal transit. DMD#05640