2-Amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists.

Abstract

Blockade of the P2Y1 receptor is important to the treatment of thrombosis with potentially improved safety margins compared with P2Y12 receptor antagonists. Investigation of a series of urea surrogates of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists, among which compound 5a was the most potent and the first non-urea analog with platelet aggregation (PA) IC50 less than 0.5 μM with 10 μM ADP. Several 2-amino-1,3,4-thiadiazole analogs such as 5b and 5f had a more favorable pharmacokinetic profile, such as higher Ctrough, lower Cl, smaller Vdss, and similar bioavailability compared with 3.

• Authors: Carol H Hu, Jennifer X Qiao, Ying Han, Tammy C Wang, Ji Hua, Laura A Price, Qimin Wu, Hong Shen, Christine S Huang, Robert Rehfuss, Ruth R Wexler, Patrick Y S Lam
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 24 Issue 11 Pg. 2481-5 (Jun 01 2014) ISSN: 1464-3405 [Electronic] England
• PMID: 24767843 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Indoles
• Piperidines
• Receptors, Purinergic P2Y1
• Thiadiazoles
• indoline
• 2-amino-1,3,4-thiadiazole

Topics

• Animals
• Dose-Response Relationship, Drug
• Humans
• Indoles (administration & dosage, chemistry)
• Molecular Structure
• Piperidines (administration & dosage, chemistry)
• Rats
• Receptors, Purinergic P2Y1 (metabolism)
• Structure-Activity Relationship
• Thiadiazoles (administration & dosage, chemistry, pharmacology)