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

Abstract

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 (fu_b = 0.19), dog (fu_b = 0.25), monkey (fu_b = 0.20) and humans (fu_b = 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.

• Clearance prediction
• CRF₁ antagonist
• hepatocytes
• in vitro–in vivo scaling
• microsomes
• pharmacokinetics

Acknowledgements

We sincerely appreciate the Novartis in vivo group for their assistance in animal studies. In addition, we thank the Novartis bioanalytical groups for quantification of drug levels in pharmacokinetic samples.