Delving into the Latest Updates on RWJ-27755 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

PPACK, RWJ 27755

Target

prothrombin

Action

inhibitors

Mechanism

prothrombin inhibitors(Prothrombin inhibitors)

Therapeutic Areas

Cardiovascular Diseases

Active Indication-

Inactive Indication

Thrombosis

Originator Organization

Johnson & Johnson

Active Organization-

Inactive Organization

Johnson & JohnsonJohnson & Johnson Pharmaceutical Research & Development LLC

License Organization-

Drug Highest PhaseDiscontinuedPreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC21H31ClN6O3

InChIKeyKWPACVJPAFGBEQ-IKGGRYGDSA-N

CAS Registry71142-71-7

Thrombin activity plays a crucial role in hemostasis, and it is tightly regulated by a system of activators and inhibitors. Active, unregulated thrombin may initiate clotting without previous vessel injury, causing thrombosis. Thrombin bound to fibrin participates in fibrinogen transformation, while its inhibition by the naturally occurring heparin–antithrombin complex is impeded. Bound thrombin activity has been detected on fibrin degradation products.

Methods:

D‐dimers were isolated using a commercial ELISA kit. Mass spectrometry was used to confirm the presence of thrombin on captured D‐dimers. D‐dimer‐bound thrombin activity was evaluated using specific substrate and inhibitors: hirudin‐PPACK and heparin–antithrombin. Groups of 72 patients and 159 controls were analyzed.

Results:

The activity of thrombin was assessed utilizing our system, demonstrating stability throughout the procedures. The thrombin concentration during fibrin polymerization was reflected in the thrombin activity levels detected on D‐dimers. Analysis of patient plasma samples indicated the feasibility of detecting low levels of active thrombin. Significant differences in D‐dimer‐bound thrombin activity were observed between subjects with chronic (controls) and acute conditions (patients).

Conclusions:

We present a proof‐of‐concept method for the evaluation of thrombin activity on circulating D‐dimers that may aid in the diagnosis of thrombotic events and the monitoring of anticoagulant therapy.

01 Apr 2025·JOURNAL OF THROMBOSIS AND HAEMOSTASIS

Replacement of a single residue changes the primary specificity of thrombin

Article

Author: Mohammed, Bassem M ; Dei Rossi, Alessia ; Deavila, Samantha ; Korolev, Sergey ; Di Cera, Enrico

BACKGROUND:

Thrombin prefers substrates carrying Arg at the site of cleavage (P1) because of the presence of D189 in the primary specificity (S1) pocket but can also cleave substrates carrying Phe at P1. The structural basis of this property is unknown.

OBJECTIVES:

Solve the X-ray structure of thrombin bound to a ligand carrying Phe at P1 and investigate the effects of replacing D189.

METHODS:

X-ray crystallography is used to solve the structure of thrombin bound to the irreversible inhibitor H-D-Phe-Pro-Phe-CH₂Cl (PPPCK). Residue D189 is mutated to Ala, Lys, Phe, and Ser.

RESULTS:

The X-ray structure of the thrombin-PPPCK complex is solved at 2.5 Å resolution and compared to the structure of thrombin bound to H-D-Phe-Pro-Arg-CH₂Cl (PPACK). PPPCK binds to thrombin in a conformation similar to that of PPACK, but Phe at P1 makes no contacts with D189. Replacement of D189 with Ala, Lys, Phe, or Ser reverses both substrate preference and stability enhancement from Arg to Phe.

CONCLUSION:

D189 in the S1 pocket confers thrombin "trypsin-like" specificity for Arg at P1. However, the S1 pocket is wide enough to also enable "chymotrypsin-like" specificity for Phe at P1. Consistent with these structural features, a single amino acid replacement (D189A) switches thrombin specificity from trypsin-like to chymotrypsin-like, converting the substrate preference from H-D-Phe-Pro-Arg-p-nitroanilide to H-D-Phe-Pro-Phe-p-nitroanilide and preferential stability enhancement from PPACK to PPPCK. The observation that thrombin specificity is controlled mainly by a single residue establishes a new paradigm in the field of trypsin-like proteases.

01 Apr 2025·FERTILITY AND STERILITY

Robotic-assisted excision of an accessory cavitated uterine malformation with indocyanine green assessment of the uterine cavity

Article

Author: Mondelli, Benedetto ; Britton, Florence ; Narayanan, Priya ; Khazali, Shaheen ; Fleischer, Kyle ; Bachi, Averyl ; Adamczyk, Michael

OBJECTIVE:

To highlight the presentation and management of a patient with dysmenorrhea caused by an accessory cavitated uterine malformation (ACUM) while also summarizing the current evidence regarding this pathology.

DESIGN:

Video article demonstrating the presentation, investigations, and surgical management of patient with an ACUM.

SUBJECTS:

A 22-year-old patient presenting with severe cyclical pain that was refractory to medical treatment was managed at a tertiary minimally invasive gynecology and endometriosis center. Ultrasound and magnetic resonance imaging showed radiological features consistent with ACUM. After appropriate counseling, the patient decided to proceed with surgical management.

INTERVENTION:

Robotic-assisted laparoscopic excision of an ACUM. The aim was to completely excise the malformation with specific steps taken to minimize blood loss, including infiltration with vasopressin and placement of temporary vascular clips, as well as prevent entry into the uterine cavity/fallopian tube. There was an incidental finding of endometriosis, which was also excised during the procedure.

MAIN OUTCOME MEASURES:

Perioperative data, including complications, histology, and symptom change.

RESULTS:

Complete excision of malformation with uncomplicated procedure and recovery. Histology confirmed ACUM. At follow-up, the patient had complete resolution of presenting symptoms.

CONCLUSION:

This video article highlights the presentation of patient with typical features for ACUM, as well as a reproducible technique for the surgical management of this malformation. The information can be used by other clinicians managing individuals with this rare presentation.

100 Deals associated with RWJ-27755

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