Design, synthesis and biological evaluation of novel 5-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives as potent potassium-competitive acid blockers

  • Bioorg Med Chem. 2022 Jun 15;64:116765. doi: 10.1016/j.bmc.2022.116765.
Xianlian Wang  1 ,  Yongmei Xu  2 ,  Zaiwei Zong  3 ,  Jinna Cai  2 ,  Chunlin Chen  2 ,  Qingwei Zhang  4 ,  Xun Sun  5 ,  Jianqi Li  6
Affiliations
  • 1. School of Pharmacy, Fudan University, Shanghai 201203, PRChina; Shanghai Medicilon Inc., 585 Chuanda Road, Shanghai 201299, PRChina.
  • 2. Shanghai Medicilon Inc., 585 Chuanda Road, Shanghai 201299, PRChina.
  • 3. Jiangsu Aosaikang Pharmaceutical CO., LTD, 699 Kejian Road, Nanjing, 211112, P.R. Jiangsu, PRChina.
  • 4. Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PRChina. Electronic address: [email protected].
  • 5. School of Pharmacy, Fudan University, Shanghai 201203, PRChina. Electronic address: [email protected].
  • 6. Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PRChina. Electronic address: [email protected].
PMID: 35477061 DOI: 10.1016/j.bmc.2022.116765
Abstract

With the aim to discover a novel potent potassium-competitive acid blocker (P-CAB) agent, a series of 5-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives were synthesized, and their H+/K+-ATPase inhibitory activities and inhibitory action on histamine-stimulated gastric acid secretion in rats were evaluated. Among the compounds synthesized, compound 3'-((3-(2-fluorophenyl)-5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-[1,1'-biphenyl]-3-carboxamide not only exhibited potent H+/K+-ATPase inhibitory activity but olso showed potent inhibitory action in vivo on histamine-stimulated gastric acid secretion. In addition, the lead compound displayed favourable oral pharmacokinetic properties in rats, which was worthy of further study as a novel P-CAB agent.

Keywords
H(+)/K(+)-ATPase; In vivo; Potassium-competitive acid blocker; Pyrazole.
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