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.

13 Feb 2014·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Small Macrocycles As Highly Active Integrin α2β1 Antagonists

Q3 · MEDICINE

Article

Author: Kohlmann, Markus ; Lindenschmidt, Andreas ; Blum, Horst ; Buning, Christian ; Halland, Nis

Starting from clinical candidates Firategrast, Valategrast, and AJM-300, a series of novel macrocyclic platelet collagen receptor α2β1 antagonists were developed. The amino acid derived low molecular weight 14-18-membered macrocycles turned out to be highly active toward integrin α2β1 with IC50s in the low nanomolar range. The conformation of the macrocycles was found to be highly important for the activity, and an X-ray crystal structure was obtained to clarify this. Subsequent docking into the metal-ion-dependent adhesion site (MIDAS) of a β1 unit revealed a binding model indicating key binding features. Macrocycle 38 was selected for further in vitro and in vivo profiling.

01 Sep 2009·Drug Development and Industrial PharmacyQ4 · MEDICINE

Functional performance of silicified microcrystalline cellulose versus microcrystalline cellulose: a case study

Q4 · MEDICINE

Article

Author: Ashish Chatterji ; Ahmad Aljaberi ; Navnit H. Shah ; Harpreet K. Sandhu

BACKGROUNDDuring the development of a tablet dosage form of an investigational compound, R411, several aspects were identified as critical quality attributes that required optimization. The use of nonsolvent processing prevented the moisture-induced physical changes in the drug product but presented manufacturing challenges related to sticking during compression and slowdown in dissolution after storage at stress conditions.AIMThe aim of this study was to evaluate silicified microcrystalline cellulose (SMCC), microcrystalline cellulose (MCC), and physical mixture of MCC-colloidal silicon dioxide (MCC/CSD at 98:2 ratio) as extragranular compression aids to address the processing and dissolution stability issues of this formulation.METHODSThe compactibility and stickiness upon compression over extended period of time as well as the dissolution of R411 formulations incorporating the aforementioned compression aids were investigated. In addition, the water sorption/desorption properties of these compression aids were determined.RESULTSAll formulations showed comparable compactibility irrespective of the compression aid used. Nevertheless, MCC alone or in a physical mixture with CSD showed sticking of the lower punches, whereas SMCC resulted in clean punch surface during extended compression runs. Furthermore, the three compression aids were compared for their effect on dissolution stability after storage at stress conditions. The formulations containing SMCC provided superior dissolution stability over the other compression aids evaluated in the study.CONCLUSIONSNovel functionalities of SMCC are presented in terms of sticking prevention while having the most beneficial effect on dissolution stability in R411 formulation.

100 Deals associated with Valategrast Hydrochloride

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 2	CA	Hoffmann-La Roche, Inc.	25 Oct 2002
Asthma	Phase 2	PR	Hoffmann-La Roche, Inc.	25 Oct 2002
Asthma	Phase 2	AU	Hoffmann-La Roche, Inc.	25 Oct 2002
Asthma	Phase 2	MX	Hoffmann-La Roche, Inc.	25 Oct 2002
Asthma	Phase 2	US	Hoffmann-La Roche, Inc.	25 Oct 2002
Multiple Sclerosis	Phase 2	-	F. Hoffmann-La Roche Ltd.	-
Multiple Sclerosis	Phase 2	-	F. Hoffmann-La Roche Ltd.	-
Multiple Sclerosis	Phase 2	US	-	-
Multiple Sclerosis	Phase 2	US	-	-

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