Author: Afatsawo, Catherine ; Risser, Francis ; Lowe, Philip John ; Hoffmann, Laurent ; Desrayaud, Sandrine ; Wipfli, Peter ; Cordier, Valerie ; Lehmann, Daniel ; Widmer, Toni ; Arabin, Philip ; Thiel, Julia ; Bigaud, Marc ; Stringer, Rowan

1. The utility of 1-aminobenzotriazole (ABT), incorporated in food, has been investigated as an approach for longer term inhibition of cytochrome P450 (P450) enzymes in mice. 2. In rats, ABT inhibits gastric emptying, to investigate this potential limitation in mice we examined the effect of ABT administration on the oral absorption of NVS-CRF38. Two hour prior oral treatment with 100 mg/kg ABT inhibited the oral absorption of NVS-CRF38, T_max was 4 hours for ABT-treated mice compared to 0.5 hours in the control group. 3. A marked inhibition of hepatic P450 activity was observed in mice fed with ABT containing food pellets for 1 month. P450 activity, as measured by the oral clearance of antipyrine, was inhibited on day 3 (88% of control), week 2 (83% of control) and week 4 (80% of control). 4. T_max values for antipyrine were comparable between ABT-treated mice and the control group, alleviating concerns about impaired gastric function. 5. Inclusion of ABT in food provides a minimally invasive and convenient approach to achieve longer term inhibition of P450 activity in mice. This model has the potential to enable pharmacological proof-of-concept studies for research compounds which are extensively metabolised by P450 enzymes.

01 Oct 2014·XenobioticaQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: Andrew Culshaw ; Rowan A Stringer ; Bindi Sohal ; Jonathan Rose ; Jeff McKenna ; Gareth Williams ; Eckhard Weber

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], a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist, 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 rat and human hepatic microsomes and cryopreserved hepatocytes from rat, dog, monkey and human, 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 enzyme (P450) suicide inhibitor 1-aminobenzotriazole, implicating P450 enzymes in the primary metabolism of this compound. 5. NVS-CRF38 is weakly bound to plasma proteins 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 rat 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.

01 May 2014·Drug Metabolism and DispositionQ2 · MEDICINE

Application of a Deuterium Replacement Strategy to Modulate the Pharmacokinetics of 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole, a Novel CRF₁Antagonist

Q2 · MEDICINE

Article

Author: Franck Picard ; Rowan A. Stringer ; Bindi Sohal ; Jeff McKenna ; Joel A. Krauser ; Olivier Kretz ; Gareth Williams

Deuterium isotope effects were evaluated as a strategy to optimize the pharmacokinetics of 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole (NVS-CRF38), a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist. In an attempt to suppress 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 intrinsic clearance (CLint) obtained for NVS-CRF38 and deuterated NVS-CRF38. In vitro kinetic isotope effects (KH/KD) were more pronounced when CLint values were calculated based on the rate of formation of the O-desmethyl metabolite (KH/KD ∼7) compared with the substrate depletion method (KH/KD ∼2). In vivo isotope effects were measured in rats 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 with 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 NVS-CRF38; however, levels of NVS-CRF38's other metabolites increased, compensating to some extent for the isotope effect.

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Indication	Highest Phase	Country/Location	Organization	Date
Anxiety Disorders	Discovery	CH	Novartis AG	-
Irritable Bowel Syndrome	Discovery	CH	Novartis AG	-

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