2-{N-[(2,4,5-trichlorophenoxy) acetyl]-N-methylamino}-3-pyrrolidinepropanamide analogs as potential antagonists of Urotensin II receptor

Abstract

The purpose of the article

To identify novel small molecule antagonists of Urotensin II receptor with acceptable pharmacological profile.

Materials and methods

Structure-activity-relationship (SAR) studies on 2-{N-[(2,4,5-trichlorophenoxy) acetyl]-N-methylamino}-3-pyrrolidinepropanamide series were conducted and shortlisted compounds were synthesized and evaluated in in vitro cell-based assays. Human and mouse Urotensin II receptor overexpressing CHO cells were used for calcium release and radioligand binding assays. Initial molecules in this series had solubility and inter-species variability issue in the calcium release assay. We, therefore, conducted SAR to overcome these 2 issues and molecules with accepted in vitro profile were evaluated further in mouse pressor response model to generate the in vivo proof of concept for UII receptor antagonization.

Results and conclusions

We report herewith identification of 2-{N-[(2,4,5-trichlorophenoxy)acetyl]-N-methylamino}-3-pyrrolidinepropanamides series to obtain novel small molecule antagonists of Urotensin II receptor with acceptable pharmacological profile.

Keywords:

• Receptors
• GPCRs
• calcium release
• radio-ligand binding
• cardiovascular
• small molecule antagonists

Acknowledgment

This research has not been funded by any specific project grant from any funding agency in the public, commercial or not-for-profit sectors.

Ethical approval

Title of ethics protocol submitted: ‘Effect of NCE’s on UII induced pressor response in mice’. Protocol was approved on 15-06-2016, (ethics Approval No: 201006) by the Institutional Animal Ethics Committee (IAEC) of Daiichi Sankyo India Pharma Pvt. Ltd.

Author contributions

All the authors contributed to the manuscript. All named authors have participated in the study to a sufficient extent and to be listed as authors and have approved the final version of the manuscript. Ajay Soni: Chemistry Lead, India, Designed the compounds, conducted Structure activity relationship studies and synthesis planning and trouble shooting. Subham Saha: Chemist: Conducted synthesis of compounds. Aditi Agarwal: Chemist: Conducted synthesis of compounds. Abdul Rehman Abdul Rauf: Chemist: Conducted Synthesis of compounds. Rakesh Kumar Singh: Conducted in vitro biology experiments for calcium release assays. Mahesh Seth: Conducted in vitro functional assays using rat aorta on organ bath set up. Shashi Kant Singh: Conducted in vivo biology experiments; mouse pressor response studies. Sandeep Sinha: Senior in vivo biology scientist. Conducted mouse pressor response studies. Raj K. Shriumalla: In vivo biology Leader. Conducted planning and execution of pressor response experiments. Shinji Marumoto^: Chemistry Lead, Japan: Provided the information on issues with previous chemotypes and efforts. Critically. Participated in overall chemistry planning. Ruchi Tandon: Biology and Program Lead. Designed, planned and trouble-shooted in vitro experiments and overall progression of program.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.