Delving into the Latest Updates on CDP-323 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

VCAM1 x α4β1 x α4β7

Action-

Mechanism

VCAM1 inhibitors(Vascular cell adhesion molecule 1 inhibitors), α4β1 antagonists(Integrin alpha-4/beta-1 antagonists), α4β7 antagonists(Integrin alpha-4/beta-7 antagonists)

Therapeutic Areas

Immune System DiseasesNervous System DiseasesOther Diseases

Active Indication-

Inactive Indication

Multiple SclerosisMultiple sclerosis relapse

Originator Organization

UCB SA

Active Organization-

Inactive Organization

UCB Pharma GmbH

Biogen, Inc.

License Organization-

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC28H29BrN4O3

InChIKeyQCYAXXZCQKMTMO-QFIPXVFZSA-N

CAS Registry455264-30-9

INTRODUCTIONThe α₄β₇ integrin is heterodimeric cell surface receptors expressed on most leukocytes. Mucosal addressing cell adhesion molecule 1(MAdCAM-1) is an exclusive ligand for α₄β₇ integrin. Areas covered: This article will highlight the progress that has been made in the discovery and development of α₄β₇ integrin inhibitors, and their use in the treatment of inflammatory bowel diseases, multiple sclerosis, asthma, hepatic disorders, human immunodeficiency virus, allergic conjunctivitis and type 1 diabetes. Expert opinion: α₄β₇ integrin inhibitors have attracted much interest for their clinical implication. Natalizumab and Vedolizumab are monoclonal antibodies (mAbs) successfully utilized clinically. Natalizumab is a mAbs of α₄-subunit blocking both α₄β₁ and α₄β₇ integrin. Vedolizumab selectively targets the α₄β₇ integrin. Several mAbs are still in the process of research and development. Among these mAbs, etrolizumab selectively against the β₇-subunit and AMG-181 specifically against the α₄β₇ integrin are the most promising anti-α₄β₇ integrin antibodies. Despite the unclear development stage of TR-14035 and R411, several low molecular compounds show bright future of further development, such as AJM300 and CDP323. In addition, results from laboratory data show that peptide inhibitors, such as peptide X, are effective α₄β₇ integrin inhibitors.

01 Sep 2015·Drug Metabolism and DispositionQ2 · MEDICINE

Cross-Species Differences in the Preclinical Pharmacokinetics of CT7758, an α4β1/α4β7 Integrin Antagonist

Q2 · MEDICINE

Article

Author: Staelens, Ludovicus ; Chanteux, Hugues ; Prakash, Chandra ; Nicolas, Jean-Marie ; Gerin, Brigitte ; Mancel, Valérie ; Boucaut, David

CT7758, a carboxylate containing α4β1/α4/β7 integrin antagonist, was characterized for its pharmacokinetic profile in various in vitro and in vivo assays in support of clinical development. The oral bioavailability of CT7758 was 4% in mice, 2% in rats, 7-55% in dogs, and 0.2% in cynomolgus monkeys. The low bioavailability in rodents and monkey results from low intestinal absorption as evidenced by a low fraction absorbed in the rat portal vein model (3%), low-to-medium permeability in Caco-2 cells (≤1.3 × 10(-6) cm/s) with evidences of polarized efflux, and high polar surface area (104 Å). In rodents and cynomolgus monkeys, the total plasma clearance was moderate to high (≥50% hepatic blood flow QH) and associated with a short elimination half-life (≤1 hour). This contrast with the dog data which showed a much lower clearance (6% QH) and a longer t1/2 (2.4 hours). The volume of distribution (Vz) also varied significantly across species with value of 5.5, 2.8, 0.24, and 0.93 l/kg in mouse, rat, dog, and cynomolgus monkey, respectively. In vitro assays demonstrated that active hepatic uptake accounted for most of the in vivo clearance and was the source of the large species variability. In vitro uptake assays predicted a total plasma clearance in humans in the low range (33% QH), a finding subsequently confirmed in the clinic. Assays in OAPT1B1-transfected cells demonstrated active uptake transport through this transporter. The prospect of limited absorption in human prompted the synthesis an ethyl ester prodrug, CDP323, which demonstrated higher in vitro permeability, increased oral bioavailability, as well as efficient in vivo release of its active moiety CT7758.

01 Jan 2014·Drug Metabolism and DispositionQ2 · MEDICINE

In Vitro Hydrolysis and Transesterification of CDP323, an α4β1/α4β7 Integrin Antagonist Ester Prodrug

Q2 · MEDICINE

Article

Author: Steven Smith ; Claude Delatour ; Jean-Marie Nicolas ; Chandra Prakash ; Hugues Chanteux ; Maria Rosa

We identified the enzyme(s) involved in the hydrolysis of the ethyl ester prodrug CDP323 (C28H29BrN403) and characterized its transesterification in the presence of ethanol with special emphasis on the risks of drug-drug interaction. The hydrolysis of CDP323 was evaluated in vitro using human liver and intestinal microsomes and recombinant human carboxylesterases (hCES1 and 2) and was shown to be approximately 20-fold higher in human liver microsomes when compared with human intestinal microsomes and in hCES1 when compared with hCES2. Nonspecific inhibitors of carboxylesterases significantly inhibited the hydrolysis of CDP323 (>80% inhibition) while specific inhibitors of CES2, acetylcholine esterase, arylesterase, and butyrylcholinesterase did not impair the hydrolysis reaction. The effect of ethanol on the kinetic parameters for hydrolysis was investigated, demonstrating that at high concentration (2%), Michaelis-Menten constant (Km), maximum velocity (Vmax), and intrinsic clearance (CLint) for the formation of the hydrolyzed product were decreased (∼40%). The use of deuterated ethanol allowed more mechanistic investigations of the transesterification mechanism and showed that the intrinsic clearance based on parent loss was not impaired in the presence of alcohol. Overall, our data demonstrate that CDP323 is mainly hydrolyzed by hCES1 and is prone to transesterification in the presence of ethanol. Transesterification mechanisms compete with hydrolysis without impairing the overall clearance of the ester prodrug. Based on in vitro results, the risk of a clinically significant drug-drug interaction with ethanol is anticipated to be low.

100 Deals associated with CDP-323

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05092

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Sclerosis	Phase 2	United Kingdom	Biogen, Inc.	01 May 2007
Multiple Sclerosis	Phase 2	Belgium	UCB Pharma GmbH	01 May 2007
Multiple Sclerosis	Phase 2	Netherlands	Biogen, Inc.	01 May 2007
Multiple Sclerosis	Phase 2	United States	Biogen, Inc.	01 May 2007
Multiple Sclerosis	Phase 2	Sweden	Biogen, Inc.	01 May 2007
Multiple Sclerosis	Phase 2	Finland	UCB Pharma GmbH	01 May 2007
Multiple Sclerosis	Phase 2	Netherlands	UCB Pharma GmbH	01 May 2007
Multiple Sclerosis	Phase 2	France	UCB Pharma GmbH	01 May 2007
Multiple Sclerosis	Phase 2	Canada	Biogen, Inc.	01 May 2007
Multiple Sclerosis	Phase 2	United States	UCB Pharma GmbH	01 May 2007