Discovery of Novel Pyrazolylpyridine Derivatives for 20-Hydroxyeicosatetraenoic Acid Synthase Inhibitors with Selective CYP4A11/4F2 Inhibition.

20-Hydroxyeicosatetraenoic acid (20-HETE) is one of the major oxidized arachidonic acid (AA) metabolites produced by cytochrome P450 (CYP) 4A11 and CYP4F2 isozymes in the human liver and kidney. Numerous studies have suggested the involvement of 20-HETE in the pathogenesis of renal diseases, and suppression of 20-HETE production by inhibition of CYP4A11 and CYP4F2 may be an attractive therapeutic strategy for renal diseases. At first, we identified methylthiazole derivative 2 as a potent dual inhibitor of CYP4A11 and CYP4F2. An optimization study of a series of derivatives with a molecular weight of around 300 to improve aqueous solubility and selectivity against drug-metabolizing CYPs while maintaining the CYP4A11- and CYP4F2-inhibitory activities led to the identification of acetylpiperidine compound 11c. Compound 11c inhibited 20-HETE production in both human and rat renal microsomes and exhibited a favorable pharmacokinetic profile. Furthermore, 11c also significantly inhibited renal 20-HETE production in Sprague-Dawley rats after oral dosing at 0.1 mg/kg.

[1]  C. R. Wang,et al.  To Be, or Not to Be, an Inhibitor: A Comparison of Azole Interactions with and Oxidation by a Cytochrome P450 Enzyme. , 2021, Inorganic chemistry.

[2]  Dongmei Zhao,et al.  Strategies for the development of highly selective cytochrome P450 inhibitors: Several CYP targets in current research. , 2019, Bioorganic & medicinal chemistry letters.

[3]  S. Bhattacharya,et al.  Lead-like Drugs: A Perspective. , 2018, Journal of medicinal chemistry.

[4]  M. Waring,et al.  Practical application of ligand efficiency metrics in lead optimisation. , 2018, Bioorganic & medicinal chemistry.

[5]  M. Edwards,et al.  Lipophilic Efficiency as an Important Metric in Drug Design. , 2018, Journal of medicinal chemistry.

[6]  Kaleab Z. Abebe,et al.  Bioactive lipid mediators in polycystic kidney disease , 2014, Journal of Lipid Research.

[7]  S. Krau.  Cytochrome p450 part 3: drug interactions: essential concepts and considerations. , 2013, The Nursing clinics of North America.

[8]  M. Waring.  Lipophilicity in drug discovery , 2010, Expert opinion on drug discovery.

[9]  C. Humblet,et al.  Escape from flatland: increasing saturation as an approach to improving clinical success. , 2009, Journal of medicinal chemistry.

[10]  M. Edwards,et al.  Using the Golden Triangle to optimize clearance and oral absorption. , 2009, Bioorganic & medicinal chemistry letters.

[11]  E. Avner,et al.  Chronic blockade of 20-HETE synthesis reduces polycystic kidney disease in an orthologous rat model of ARPKD. , 2009, American journal of physiology. Renal physiology.

[12]  H. Abboud,et al.  Mechanisms of Podocyte Injury in Diabetes , 2009, Diabetes.

[13]  Jean-Didier Maréchal,et al.  How do azoles inhibit cytochrome P450 enzymes? A density functional study. , 2008, The journal of physical chemistry. A.

[14]  E. Avner,et al.  20-HETE mediates proliferation of renal epithelial cells in polycystic kidney disease. , 2008, Journal of the American Society of Nephrology : JASN.

[15]  D. Manallack,et al.  Prediction of drug solubility from molecular structure using a drug-like training set , 2008, SAR and QSAR in environmental research.

[16]  Toshio Nakamura,et al.  Pyrazole derivatives as new potent and selective 20-hydroxy-5,8,11,14-eicosatetraenoic acid synthase inhibitors. , 2004, Bioorganic & medicinal chemistry.

[17]  T. Ishii,et al.  Design and synthesis of 1-(4-benzoylphenyl)imidazole derivatives as new potent 20-HETE synthase inhibitors. , 2004, Bioorganic & medicinal chemistry letters.

[18]  Toshio Nakamura,et al.  Imidazole derivatives as new potent and selective 20-HETE synthase inhibitors. , 2004, Bioorganic & medicinal chemistry letters.

[19]  Toshio Nakamura,et al.  Pyrazole and isoxazole derivatives as new, potent, and selective 20-hydroxy-5,8,11,14-eicosatetraenoic acid synthase inhibitors. , 2003, Journal of medicinal chemistry.

[20]  R. Roman,et al.  Localization of cytochrome P-450 4A isoforms along the rat nephron. , 1998, American journal of physiology. Renal physiology.

[21]  J. Falck,et al.  20-Hydroxyeicosatetraenoic acid is formed in response to EGF and is a mitogen in rat proximal tubule. , 1995, The American journal of physiology.

[22]  J. Falck,et al.  Metabolism of 20-hydroxyeicosatetraenoic acid by cyclooxygenase. Formation and identification of novel endothelium-dependent vasoconstrictor metabolites. , 1989, The Journal of biological chemistry.

[23]  B. Masters,et al.  20-Hydroxyeicosatetraenoic acid is an endogenous vasoconstrictor of canine renal arcuate arteries. , 1993, Circulation research.