A Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Short and Long Intravenous Infusion Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of BMS- 962212 in Healthy Subjects

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics following increasing doses of 2 h (Part A) and 5 day (Part B) continuous IV infusions of BMS-962212 in healthy subjects across the expected pharmacodynamic dose range.

Start Date18 Nov 2013

Sponsor / Collaborator

Bristol Myers Squibb Co.

100 Clinical Results associated with BMS-962212

100 Translational Medicine associated with BMS-962212

100 Patents (Medical) associated with BMS-962212

Literatures (Medical) associated with BMS-962212

10 Mar 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

Targeting the S2 Subsite Enables the Structure-Based Discovery of Novel Highly Selective Factor XIa Inhibitors

Q1 · MEDICINE

Article

Author: Hou, Shuzeng ; Duan, Yajun ; Kong, Yi ; Xie, Zhouling ; Han, Jihong ; Yao, Ningning ; Jia, Zhiping ; Yang, Xiaoxiao ; Liao, Chenzhong ; Tian, Yongbin

FXIa inhibition has been a promising strategy for treating thrombotic diseases. Up to date, many small-molecule FXIa inhibitors have been identified; however, most of them exhibit undesirable selectivity over the homologous plasma kallikrein (PKal). By employing structure-based drug design strategies, we identified many novel selective FXIa inhibitors that have extra interactions with the S2 subsite of FXIa. Among them, compound 35 displayed good inhibitory activity against FXIa and high selectivity over PKal and even several other serine proteases. Additionally, 35 showed significant anticoagulant activity toward the intrinsic pathway without affecting the extrinsic pathway. In vivo, 35 exhibited significant antithrombotic activity without increasing the bleeding risk and obvious toxicity in mice, demonstrating that it could be a promising candidate for further research. This study first demonstrates the importance of the S2 subsite of FXIa, paving the way to design highly selective FXIa inhibitors for clinical uses.

01 Aug 2021·Journal of Chromatography AQ2 · CHEMISTRY

The effect of water on the large-scale supercritical fluid chromatography purification of two factor XIa active pharmaceutical ingredients

Q2 · CHEMISTRY

Article

Author: Yip, Henry ; Sun, Dawn ; Mathur, Arvind ; Li, Peng ; Zhang, Huiping ; Wu, Dauh-Rurng ; Kempson, James ; Hou, Xiaoping

BMS-962212, a parenteral Factor XIa inhibitor, was scaled-up for toxicity studies. Two steps of supercritical fluid chromatography (SFC) were developed for the chiral resolution of the penultimate and achiral purification of final active pharmaceutical ingredient (API), BMS-962212. A robust SFC process using Chiralcel OD-H with methanol-acetonitrile as modifier in CO₂ was established to achieve a stable and uninterrupted operation with reduced mobile phase viscosity and system pressure drop. More than 230 g of the racemic penultimate was chirally resolved to reach >99% chiral purity, ready for final tert-butyl ester deprotection to provide the API. There were a significant number of impurities in BMS-962212 generated from the final step that needed to be removed. In contrast to conventional SFC conditions, an SFC method exploiting water and ammonia as additives in both the mobile phase and sample solution was developed to accomplish purification and desalting (i.e. removing TFA) of the zwitterionic API in one step. Water as an additive eliminated salt precipitation and improved the resolution while ammonia contributed to the desalting, details of which will be discussed in this article. A throughput of 2 g/h was achieved, and >80 g of the crude API was purified. The same strategy was applied to another Factor XIa API (compound A) and its penultimate.

01 May 2018·British Journal of Clinical PharmacologyQ2 · MEDICINE

First‐in‐human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS‐962212, a direct, reversible, small molecule factor XIa inhibitor in non‐Japanese and Japanese healthy subjects

Q2 · MEDICINE

Article

Author: Cirincione, Brenda ; Frost, Charles E. ; Seiffert, Dietmar ; Perera, Vidya ; Knabb, Robert M. ; DeSouza, Mary ; Lee, John ; Ueno, Takayo ; Wang, Zhaoqing ; Ma, Xuewen ; Yones, Cynthia ; Zhao, Yue ; LaCreta, Frank P. ; Russo, Cesare ; Luettgen, Joseph M. ; Mugnier, Pierre ; Frost, Robert J. A.

AimsThe aims of the present study were to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS‐962212, a first‐in‐class factor XIa inhibitor, in Japanese and non‐Japanese healthy subjects.MethodsThis was a randomized, placebo‐controlled, double‐blind, sequential, ascending‐dose study of 2‐h (part A) and 5‐day (part B) intravenous (IV) infusions of BMS‐962212. Part A used four doses (1.5, 4, 10 and 25 mg h−1) of BMS‐962212 or placebo in a 6:2 ratio per dose. Part B used four doses (1, 3, 9 and 20 mg h−1) enrolling Japanese (n = 4 active, n = 1 placebo) and non‐Japanese (n = 4 active, n = 1 placebo) subjects per dose. The PK, PD, safety and tolerability were assessed throughout the study.ResultsBMS‐962212 was well tolerated; there were no signs of bleeding, and adverse events were mild. In parts A and B, BMS‐962212 demonstrated dose proportionality. The mean half‐life in parts A and B ranged from 2.04 to 4.94 h and 6.22 to 8.65 h, respectively. Exposure‐dependent changes were observed in the PD parameters, activated partial thromboplastin time (aPTT) and factor XI clotting activity (FXI:C). The maximum mean aPTT and FXI:C change from baseline at 20 mg h−1 in part B was 92% and 90%, respectively. No difference was observed in weight‐corrected steady‐state concentrations, aPTT or FXI:C between Japanese and non‐Japanese subjects (P > 0.05).ConclusionBMS‐962212 has tolerability, PK and PD properties suitable for investigational use as an acute antithrombotic agent in Japanese or non‐Japanese subjects.

100 Deals associated with BMS-962212

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Phase 2	-	Bristol Myers Squibb Co.	-

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