Synthesis and biological evaluation of pyrazolo[3,4-b]pyridine-3-yl pyrimidine derivatives as sGC stimulators for the treatment of pulmonary hypertension

Liang Li; Wenpeng Zhang; Feng Lin; Xinqiang Lu; Wei Chen; Xingzhou Li; Xinbo Zhou; Ruibin Su; Lili Wang; Zhibing Zheng; Song Li

doi:10.1016/j.ejmech.2019.04.014

Synthesis and biological evaluation of pyrazolo[3,4-b]pyridine-3-yl pyrimidine derivatives as sGC stimulators for the treatment of pulmonary hypertension

Eur J Med Chem. 2019 Jul 1:173:107-116. doi: 10.1016/j.ejmech.2019.04.014. Epub 2019 Apr 10.

Authors

Liang Li¹, Wenpeng Zhang², Feng Lin³, Xinqiang Lu², Wei Chen², Xingzhou Li⁴, Xinbo Zhou⁴, Ruibin Su², Lili Wang², Zhibing Zheng⁵, Song Li⁴

Affiliations

¹ State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, PR China; Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China.
² State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China.
³ Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China.
⁴ State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China; Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China.
⁵ State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China; Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, PR China. Electronic address: mailto:zzbcaptain@aliyun.com.

PMID: 30995566
DOI: 10.1016/j.ejmech.2019.04.014

Abstract

A series of new pyrazolo[3,4-b]pyridin-3-yl pyrimidine derivatives were synthesized and evaluated for the activation of sGC. Compared with riociguat, compound 13a exhibited equivalent in vitro activity on preconstricted rat thoracic aorta rings and in Rat heart Langendorff preparation. Compound 13a also showed acceptable PK profiles, which might become a promising candidate for the treatment of pulmonary hypertension.

Keywords: Pulmonary hypertension; Riociguat; pyrazolo[3,4-b]pyridine-3-yl pyrimidine derivatives; sGC stimulators.

MeSH terms

Animals
Antihypertensive Agents / chemical synthesis
Antihypertensive Agents / chemistry
Antihypertensive Agents / pharmacology*
Dose-Response Relationship, Drug
Hypertension, Pulmonary / drug therapy*
Hypertension, Pulmonary / metabolism
Male
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Rats
Rats, Sprague-Dawley
Soluble Guanylyl Cyclase / metabolism*
Structure-Activity Relationship

Substances

Antihypertensive Agents
Pyrazoles
Pyridines
Pyrimidines
pyrazolo(3,4-b)pyridine
Soluble Guanylyl Cyclase
pyrimidine