2. Academic Validation
  3. 5-Chlorothiophene-2-carboxylic acid [(S)-2-[2-methyl-3-(2-oxopyrrolidin-1-yl)benzenesulfonylamino]-3-(4-methylpiperazin-1-yl)-3-oxopropyl]amide (SAR107375), a selective and potent orally active dual thrombin and factor Xa inhibitor

5-Chlorothiophene-2-carboxylic acid [(S)-2-[2-methyl-3-(2-oxopyrrolidin-1-yl)benzenesulfonylamino]-3-(4-methylpiperazin-1-yl)-3-oxopropyl]amide (SAR107375), a selective and potent orally active dual thrombin and factor Xa inhibitor

  • J Med Chem. 2013 Dec 12;56(23):9441-56. doi: 10.1021/jm4005835.
Jerome Meneyrol 1,  Markus Follmann,  Gilbert Lassalle,  Volkmar Wehner,  Guillaume Barre,  Tristan Rousseaux,  Jean-Michel Altenburger,  Frederic Petit,  Zsolt Bocskei,  Herman Schreuder,  Nathalie Alet,  Jean-Pascal Herault,  Laurence Millet,  Frederique Dol,  Peter Florian,  Paul Schaeffer,  Freddy Sadoun,  Sylvie Klieber,  Christophe Briot,  Françoise Bono,  Jean-Marc Herbert
Affiliations

Affiliation

  • 1 Sanofi-Aventis R&D , 195 Route d'Espagne, 31036 Toulouse Cedex, France.
PMID: 24175584 DOI: 10.1021/jm4005835
Abstract

Compound 15 (SAR107375), a novel potent dual Thrombin and Factor Xa Inhibitor resulted from a rational optimization process. Starting from compound 14, with low Factor Xa and modest anti-thrombin inhibitory activities (IC50's of 3.5 and 0.39 μM, respectively), both activities were considerably improved, notably through the incorporation of a neutral chlorothiophene P1 fragment and tuning of P2 and P3-P4 fragments. Final optimization of metabolic stability with microsomes led to the identification of 15, which displays strong activity in vitro vs Factor Xa and Thrombin (with Ki's of 1 and 8 nM, respectively). In addition 15 presents good selectivity versus related serine proteases (roughly 300-fold), including trypsin (1000-fold), and is very active (0.39 μM) in the Thrombin generation time (TGT) coagulation assay in human platelet rich plasma (PRP). Potent in vivo activity in a rat model of venous thrombosis following iv and, more importantly, po administration was also observed (ED50 of 0.07 and 2.8 mg/kg, respectively). Bleeding liability was reduced in the rat wire coil model, more relevant to arterial thrombosis, with 15 (blood loss increase of 2-fold relative to the ED80 value) compared to rivaroxaban 2 and dabigatran etexilate 1a.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z