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

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

  • J Med Chem. 2022 Nov 10;65(21):14599-14613. doi: 10.1021/acs.jmedchem.2c01089.
Madoka Kawamura 1,  Yohei Kobashi 1,  Hiroaki Tanaka 1,  Ayako Bohno-Mikami 1,  Makoto Hamada 1,  Yuji Ito 1,  Takashi Hirata 1,  Hiroki Ohara 1,  Naoki Kojima 1,  Hiroko Koretsune 1,  Emi Gunji 1,  Takuya Fukunaga 1,  Shoko Inatani 2,  Yoshitaka Hasegawa 2,  Akinori Suzuki 3,  Teisuke Takahashi 1,  Hiroyuki Kakinuma 1
Affiliations

Affiliations

  • 1 Discovery Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-Cho, Kita-Ku, Saitama, Saitama331-9530, Japan.
  • 2 Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-Cho, Kita-Ku, Saitama, Saitama331-9530, Japan.
  • 3 Pharmaceutical Sciences Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-Cho, Kita-Ku, Saitama, Saitama331-9530, Japan.
PMID: 36318660 DOI: 10.1021/acs.jmedchem.2c01089
Abstract

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.

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