2-Amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists.
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.
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.
Carol H
CH
Hu
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.
Jennifer X
JX
Qiao
Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
Ying
Y
Han
Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
Tammy C
TC
Wang
Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
Ji
J
Hua
Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
Laura A
LA
Price
Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
Qimin
Q
Wu
Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
Hong
H
Shen
Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
Christine S
CS
Huang
Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
Robert
R
Rehfuss
Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
Ruth R
RR
Wexler
Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA.
Patrick Y S
PY
Lam
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry*; D015394:Molecular Structure; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
D007211:Indoles; D010880:Piperidines; D058472:Receptors, Purinergic P2Y1; D013830:Thiadiazoles; C057812:indoline; C010852:2-amino-1,3,4-thiadiazole
2-Amino-1,3,4-thiadiazoles; Antiplatelet; P2Y(1) receptor antagonist; Structure–activity relationship (SAR); Urea mimetics