Identification of 2-substituted pyrrolo[1,2-b]pyridazine derivatives as new PARP-1 inhibitors

Hao-Yue Xiang; Jian-Yang Chen; Xia-Juan Huan; Yi Chen; Zhao-Bing Gao; Jian Ding; Ze-Hong Miao; Chun-Hao Yang

doi:10.1016/j.bmcl.2020.127710

Identification of 2-substituted pyrrolo[1,2-b]pyridazine derivatives as new PARP-1 inhibitors

Bioorg Med Chem Lett. 2021 Jan 1:31:127710. doi: 10.1016/j.bmcl.2020.127710. Epub 2020 Nov 24.

Authors

Hao-Yue Xiang¹, Jian-Yang Chen², Xia-Juan Huan², Yi Chen³, Zhao-Bing Gao⁴, Jian Ding², Ze-Hong Miao⁵, Chun-Hao Yang⁶

Affiliations

¹ College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan 410083, PR China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
³ Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
⁴ Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: zhmiao@simm.ac.cn.
⁶ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: chyang@simm.ac.cn.

PMID: 33246105
DOI: 10.1016/j.bmcl.2020.127710

Abstract

A library of new 2-substituted pyrrolo[1,2-b]pyridazine derivatives were rapidly assembled and identified as PARP inhibitors. Structure-activity relationship for this class of inhibitor resulted in the discovery of most potent compounds 15a and 15b that exhibited about 29- and 5- fold selective activity against PARP-1 over PARP-2 respectively. The antiproliferative activity of the as-prepared compounds were demonstrated by further celluar assay in BRCA2-deficient V-C8 and BRCA1-deficient MDA-MB-436 cell lines, displaying that compound 15b could robustly reduce the corresponding cell proliferation and growth with CC₅₀s of 340 and 106 nM respectively. The PK property of 15b was also investigated here.

Keywords: Antiproliferative; Cancer; PARP inhibitors; Pyrrolo[12-b]pyridazine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors*
Poly (ADP-Ribose) Polymerase-1 / metabolism
Poly(ADP-ribose) Polymerase Inhibitors / chemical synthesis
Poly(ADP-ribose) Polymerase Inhibitors / chemistry
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
Pyridazines / chemical synthesis
Pyridazines / chemistry
Pyridazines / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Pyridazines
Pyrroles
Pyrrolopyridazine
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1