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

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

  • Bioorg Med Chem Lett. 2014 Jun 1;24(11):2481-5. doi: 10.1016/j.bmcl.2014.04.011.
Carol H Hu 1,  Jennifer X Qiao 2,  Ying Han 3,  Tammy C Wang 3,  Ji Hua 3,  Laura A Price 3,  Qimin Wu 3,  Hong Shen 3,  Christine S Huang 3,  Robert Rehfuss 3,  Ruth R Wexler 3,  Patrick Y S Lam 3
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA. Electronic address: carol.hu@bms.com.
  • 2 Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA. Electronic address: jennifer.qiao@bms.com.
  • 3 Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
PMID: 24767843 DOI: 10.1016/j.bmcl.2014.04.011
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.

Keywords

2-Amino-1,3,4-thiadiazoles; Antiplatelet; P2Y(1) receptor antagonist; Structure–activity relationship (SAR); Urea mimetics.

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