Identification of 1-{2-[4-chloro-1'-(2,2-dimethylpropyl)-7-hydroxy-1,2-dihydrospiro[indole-3,4'-piperidine]-1-yl]phenyl}-3-{5-chloro-[1,3]thiazolo[5,4-b]pyridin-2-yl}urea, a potent, efficacious and orally bioavailable P2Y(1) antagonist as an antiplatelet agent

Yoon T Jeon; Wu Yang; Jennifer X Qiao; Ling Li; Rejean Ruel; Carl Thibeault; Sheldon Hiebert; Tammy C Wang; Yufeng Wang; Yajun Liu; Charles G Clark; Henry S Wong; Juliang Zhu; Dauh-Rurng Wu; Dawn Sun; Bang-Chi Chen; Arvind Mathur; Silvi A Chacko; Mary Malley; Xue-Qing Chen; Hong Shen; Christine S Huang; William A Schumacher; Jeffrey S Bostwick; Anne B Stewart; Laura A Price; Ji Hua; Danshi Li; Paul C Levesque; Dietmar A Seiffert; Robert Rehfuss; Ruth R Wexler; Patrick Y S Lam

doi:10.1016/j.bmcl.2014.01.066

Identification of 1-{2-[4-chloro-1'-(2,2-dimethylpropyl)-7-hydroxy-1,2-dihydrospiro[indole-3,4'-piperidine]-1-yl]phenyl}-3-{5-chloro-[1,3]thiazolo[5,4-b]pyridin-2-yl}urea, a potent, efficacious and orally bioavailable P2Y(1) antagonist as an antiplatelet agent

Bioorg Med Chem Lett. 2014 Mar 1;24(5):1294-8. doi: 10.1016/j.bmcl.2014.01.066. Epub 2014 Jan 31.

Authors

Yoon T Jeon¹, Wu Yang², Jennifer X Qiao³, Ling Li¹, Rejean Ruel¹, Carl Thibeault¹, Sheldon Hiebert¹, Tammy C Wang¹, Yufeng Wang¹, Yajun Liu¹, Charles G Clark¹, Henry S Wong¹, Juliang Zhu¹, Dauh-Rurng Wu¹, Dawn Sun¹, Bang-Chi Chen¹, Arvind Mathur¹, Silvi A Chacko⁴, Mary Malley⁴, Xue-Qing Chen⁴, Hong Shen⁴, Christine S Huang⁴, William A Schumacher⁵, Jeffrey S Bostwick⁵, Anne B Stewart⁵, Laura A Price⁵, Ji Hua⁵, Danshi Li⁴, Paul C Levesque⁴, Dietmar A Seiffert⁵, Robert Rehfuss⁵, Ruth R Wexler¹, Patrick Y S Lam¹

Affiliations

¹ Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
² Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA. Electronic address: wu.yang@bms.com.
³ Discovery Chemistry, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA. Electronic address: jennifer.qiao@bms.com.
⁴ Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
⁵ Discovery Biology, Cardiovascular, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.

PMID: 24513044
DOI: 10.1016/j.bmcl.2014.01.066

Abstract

Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.

Keywords: Antiplatelet agent; P2Y(1) antagonist; Spiropiperidinylindolines.

MeSH terms

Administration, Oral
Animals
Dogs
Half-Life
Macaca fascicularis
Phenylurea Compounds / chemistry*
Phenylurea Compounds / pharmacokinetics
Phenylurea Compounds / pharmacology
Phenylurea Compounds / therapeutic use
Platelet Aggregation / drug effects
Platelet Aggregation Inhibitors / chemistry*
Platelet Aggregation Inhibitors / pharmacokinetics
Platelet Aggregation Inhibitors / pharmacology
Platelet Aggregation Inhibitors / therapeutic use
Purinergic P2Y Receptor Antagonists / chemistry*
Purinergic P2Y Receptor Antagonists / pharmacokinetics
Purinergic P2Y Receptor Antagonists / pharmacology
Purinergic P2Y Receptor Antagonists / therapeutic use
Rats
Receptors, Purinergic P2Y1 / chemistry*
Receptors, Purinergic P2Y1 / metabolism
Structure-Activity Relationship
Thiazoles / chemistry*
Thiazoles / pharmacokinetics
Thiazoles / pharmacology
Thiazoles / therapeutic use
Thrombosis / drug therapy
Urea / analogs & derivatives*
Urea / pharmacokinetics
Urea / pharmacology
Urea / therapeutic use

Substances

Phenylurea Compounds
Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
Receptors, Purinergic P2Y1
Thiazoles
Urea