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The Discovery of CDP323, a Potent Alpha4 Integrin Antagonist Stuart Bailey, Roger Palframan, Gillian Watt and John Porter*

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The Discovery of CDP323, a Potent Alpha4 Integrin Antagonist Stuart Bailey, Roger Palframan, Gillian Watt and John Porter* Current Immunology Reviews, 2012, 8, 135-140 135 The Discovery of CDP323, a Potent Alpha4 Integrin Antagonist Stuart Bailey, Roger Palframan, Gillian Watt and John Porter* UCB Celltech, 216 Bath Road, Slough SL1 3WE, UK Abstract: Blocking the action of alpha4 integrin would be expected to be of therapeutic benefit in the management of autoimmune diseases. Although this has been successfully demonstrated in the clinic with a monoclonal antibody for the treatment of multiple sclerosis, there are no small molecule alpha4 integrin antagonists on the market despite significant endeavour over the last 15-20 years. We review our efforts in this area, starting from a cyclic peptide based on an integrin recognition sequence and culminating in the low molecular weight clinical candidate, CDP323. We include a discussion on pre-clinical pharmacological data for CDP323. Keywords: Alpha4 integrin, CDP323, integrin antagonists, VLA-4 integrin. INTRODUCTION known as Very Late Antigen 4, VLA-4) is formed by the interaction between alpha4 (CD49d) and beta1 (CD29) Alpha4 integrin is a clinically validated target for certain integrin subunits. Additionally, alpha4 can also associate autoimmune diseases. The anti-alpha4 integrin monoclonal ® with a beta7 subunit. The primary ligands for alpha4beta1 antibody (mAb) natalizumab (Tysabri , Biogen Idec/Elan) are the endothelial surface protein vascular cell adhesion has shown significant therapeutic efficacy in patients with molecule (VCAM) and the alternatively spliced connecting multiple sclerosis (MS) [1] and Crohn’s disease [2]. The segment 1 (CS-1) of the extracellular matrix protein alpha4 integrin subunit is expressed on the surface of fibronectin (FN). Alpha4beta7 (also known as lymphocyte leukocytes, including T-lymphocytes and monocytes, Peyer’s patch adhesion molecule 1, LPAM-1) binds to the forming non-covalent heterodimers with beta1 and beta7 mucosal vascular addressin cell adhesion molecule-1 integrin subunits to create functional cell adhesion molecules (MAdCAM-1) expressed on gut-associated lymphoid tissue [3]. Alpha4beta1 and alpha4beta7 are important for cell as well as FN and VCAM. Alpha4beta1 recognises key migration into tissues under both physiologic and pathologic amino acid sequences within the ligands, namely QIDS in conditions [4]. The pharmacologic mechanism of action of VCAM and LDV in the CS-1 of FN. natalizumab is thought to be antagonism of leukocyte alpha4beta1 and/or alpha4beta7 interaction with their The small-molecule alpha4 integrin antagonists that have counter receptors on endothelial cells, causing inhibition of so far been progressed into clinical trials can be classified pathogenic leukocyte migration into tissue [5]. into two structural types: (1) mimics of the LDV sequence, for example, the highly selective alpha4 integrin antagonist Monoclonal antibodies are currently delivered almost Bio-1211 [11, 12] compound 1 or (2) N-acylphenylalanine- exclusively by intravenous or subcutaneous routes of based compounds such as valategrast (R411) [13] compound injection, can be immunogenic [6] and relatively expensive 2, many of which exhibit dual inhibitory activity for integrin to manufacture. The successful clinical development of an alpha4beta1, as well as alpha4beta7. Our starting point, orally bioavailable, low molecular weight, potent and however, was the cyclic peptide R*CDThioPC* compound 3 selective alpha4 integrin antagonist would represent the [14] and we now summarize the medicinal chemistry that led next-generation of therapeutics for diseases where alpha4 to the clinical candidate CDP323 as well as some of the integrins have been shown to play a pivotal role [7]. Thus, associated pharmacology. over the past 15 years there have been intensive efforts to discover and develop new candidate low molecular weight R*CDThioPC* compound 3, Table 1, is active against alpha4 integrin antagonists [8]. However, in 2010 there are alpha4beta1 but also binds to the related integrin alpha5beta1 only a few candidates in clinical trials for the treatment of (VLA-5), presumably because of its derivation from the MS and Crohn’s disease, and none of these compounds has RGD sequence. RGD is another recognition sequence for a yet been approved in any indication. subset of integrins including alpha5beta1 but not alpha4beta1 or alpha4beta7. Replacing the arginine residue Structurally, integrins are formed by the non-covalent with more lipophilic groups led to more active and selective association of alpha and beta subunits [9]; currently, 18 analogues, for example, the cyclic tetrapeptide alpha units and 8 beta subunits are known and these can (adamantylcarbonyl)-C*DThioPC*-OH compound 4, Table assemble in a restricted manner, dependent on cell type, to 1. A substantial amount of work was done in exploring the generate 24 different heterodimeric human family members. SAR of these cyclic peptides but the key observation was to They can be grouped according to subunit composition or establish that the cysteine residue’s carboxylic acid was ligand binding properties [10]. Alpha4beta1 integrin (also important for activity. The aspartic acid residue, in contrast, could be replaced with an alanine, as for example in compound 5, Table 1, with only a small loss in potency [15]. *Address correspondence to this author at the UCB Celltech, 216 Bath Road, Slough SL1 3WE, UK; Tel: +44 1753 807429; Fax: +44 1753 The essential carboxylic acid presumably mimics the 536632; E-mail: [email protected] 1875-631X/12 $58.00+.00 © 2012 Bentham Science Publishers 136 Current Immunology Reviews, 2012, Vol. 8, No. 2 Bailey et al. CO H O 2 O CO H thioproline with homo-proline brought a reduction in H H 2 N N O N N activity, suggesting that the orientation of the two amide H O O carbonyl groups adjacent to the proline moiety was optimum N N H H in compound 8. We subsequently prepared a number of analogues in which the adamantyl carbonyl and thioproline 1 Bio1211 H2N NH groups were varied but none of these proved more active. Cl Cross screening against the integrins a5beta1 and HN CO2H O O alphaIIbbetaIIIa showed that these compounds were O HN Cl HN H selective for alpha4beta1 (IC50 >800 and 400 μM, N N O N O H respectively). O Cl O S HN O RO Table 1. In Vitro Activities for Compounds 3-8 N S H CO2H O Cl 3 Compound Alpha4 Beta1/VCAM IC50 (nM) Cell IC50 (nM) 2 R=CH2CH2N(C2H5)2 Valategrast, R411 3 7650 nd R O 4 170 nd HN H N N 5 330 nd O O S HN O 6 7300 nd S CO2H 7 4100 nd 4 R=CO2H 8 280 nd 5 R=H nd: not done. Having established the importance of the N-acetyl-l- H H N R N thioproline residue in conveying activity against the O O alpha4beta1 integrin, we derivatized this moiety with a S S S S O number of -amino acids, introducing a protein-based, O O ligand binding screen alongside the cell-based, adhesion N HO2C N HO C N H 2 H assay. This work [16] led to the O-benzylated tyrosine S analogue 9, Table 2, which afforded improved potency in 8 6 R=CO2H both the protein and cell based assays. An important 7 R=H breakthrough was the discovery that an `L to D' switch in the stereochemistry of the thioproline residue afforded a carboxylic acid residue in the recognition sequence of magnitude improvement in activity of compound 10, Table alpha4beta1’s ligands. Although cyclic peptides have been 2. When the analogous stereochemical switch was performed developed as therapeutic drugs, they generally suffer from on the tyrosine residue in a related analogue, a decrease in poor pharmacokinetics and rapid metabolism. Indeed, activity of two orders of magnitude was observed. plasma stability studies on compound 3 revealed rapid Incorporation of the 2, 6-dichlorobenzyl compound 11, degradation (t 3 min). Although depeptidisation and Table 2 (initially introduced to improve plasma stability of stabilising modifications were considered, this approach, in the benzoyl derivative) improved activity, particularly in the our opinion, would be both demanding and without cell-based assay. Cross-screening against a panel of 7 other sufficient guarantee of success. Instead, we attempted to integrins showed that compound 11 was over 6000 fold more determine which were the key pharmacophoric groups in a selective for alpha4beta1, with the exception of the related cyclic peptide such as 5 and use this information to design integrin alpha4beta7, where it displayed a 5-fold selectivity. simpler, acyclic structures more amenable to SAR studies. Compound 11 was active in a sheep model of antigen During the initial experiments, we isolated N,N- induced early and late phase bronchoconstriction followed diadamantylcarbonyl-l-cystine 6, Table 1, as a by-product. by an airway hyperresponsiveness to inhaled methacholine. This compound displayed significant activity prompting When administered orally, 2 h prior to antigen challenge, further investigation. More interestingly, the analogue 7, compound 11 (30 mg/kg) caused a marked inhibition of both Table 1, in which one of the carboxylic acid groups was early and late phase bronchoconstriction and blocked the removed completely, was also active and represented a expression of airway hyperresponsiveness. Replacement of significantly simplified structure. The inhibitors 6 and 7 had the benzyl group with a dichloropyridylamide, compound a relationship to the potent cyclic peptides, for example 12, Table 2, gave even greater potency and selectivity compound 4, with the essential cysteine-derived carboxylic (though retaining alpha4beta7 activity). acid common to both structures and the proximal Disappointingly, these compounds and their analogues adamantylcarbonyl group of the acyclic analogues displayed rapid clearance in a number of species thereby mimicking the (thio)proline residues of the cyclic peptides. hindering further development. That this rapid clearance was Support for this idea was delivered by making the a result of an active transport mechanism was shown by the appropriate proline acyclic analogues, for example presence in the bile of only trace amounts of metabolites compound 8, Table 1.
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