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Synthesis and SAR of pyridazinone-substituted phenylalanine amide α4 integrin antagonists
Abstract
Structural modification and cellular adhesion inhibition activities of pyridazinone-substituted phenylalanine amide alpha(4) integrin antagonists are described. Functionality requirements for the arylamide moiety and the carboxylic acid group were demonstrated. The study also revealed novel structure-activity relationships (SAR) for arylated pyridazinones. A correlation between bioavailability and permeability was also explored. A selected compound showed effectiveness in a mouse leukocytosis study.
... A common key structural element of both pharmacophores is a carboxylic acid group that is key for the binding to the Mg 2+ of the metal-ion-dependent adhesion site of the integrin (Takagi, 2007). Removing this carboxylic group invariably reduced the potency of the antagonist (Gong et al., 2008). Unfortunately, this ionized carboxylate group combined with high molecular weight, high hydrogen bound count has been responsible for poor intestinal absorption and/or rapid clearance (Davenport and Munday, 2007). ...
... Poor intestinal absorption and extensive biliary clearance have been recurring issues in the development of small molecule VLA-4 antagonists (Davenport and Munday, 2007). Several physicochemical properties have been discussed as potentially involved in the low intestinal absorption of VLA-4 antagonists, such as high molecular weight (Muller et al., 2001;Davenport and Munday, 2008), low lipophilicity degree (Chiba et al., 2006a,b;2007), and presence of a carboxylate function (Davenport and Munday, 2007;Gong et al., 2008). Polar surface area (sum of hydrogen bond donor and acceptor groups) is another readily accessible descriptor used to predict intestinal absorption (Veber et al., 2002;Bergstrom et al., 2003), which could also play a role in VLA-4 antagonist pharmacokinetics (Davenport and Munday, 2007). ...
... Many carboxylatecontaining VLA-antagonists have been optimized as prodrugs. While in some cases prodrugs offered better intestinal permeability and increased exposure after oral (Huryn et al., 2004a,b;Dyatkin et al., 2005;Venkatraman et al., 2009;Reger et al., 2010), some other attempts remained unfruitful or of limited benefit (Chiba et al., 2006a,b;Gong et al., 2006Gong et al., , 2008). As demonstrated with other ester prodrugs (Chanteux et al., 2003), the present data showed that CDP323 prodrug increased mass transfer across biologic membranes compared with the carboxylic acid derivative CT7758. ...
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 (≤ 1.3x10(-6) cm/sec) 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 h). This contrast with the dog data which showed a much lower clearance (6 % Qh) and a longer t1/2 (2.4 h). 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.
The American Society for Pharmacology and Experimental Therapeutics.
... This is mainly due to the more flexible nature of pyridazine moiety for structural tuning. Several reports have emphasized the pharmacological usefulness of pyridazinone derivatives and a large number of contributions in various fields of interest, namely anticancer, antinociceptive, anti-inflammatory, analgesic, antidepressant, hypotensive, antimicrobial, and antioxidant activities [11][12][13][14][15][16][17]. Apart from these potential utilities, these pyridazine units are known for their physicochemical properties. ...
Three novel fluorophores i.e. (E)-4-(2-chlorobenzyl)-6-(4-chlorostyryl)pyridazin-3(2H)-one (4a), (E)-6-(4-chlorostyryl)-4-(4-methoxybenzyl)pyridazin-3(2H)-one (4b) and (E)-4-benzyl-6-(4-chlorostyryl)pyridazin-3(2H)-one (4c) were synthesized and characterized by FT-IR, ¹H-NMR, ¹³C-NMR and mass spectrometry. To gain insights into the structure-property relationship, a detailed computational study is taken up here at the B3LYP/6-31+g(d,p) level. Frontier molecular orbital (FMO) analysis and natural bond orbital analysis (NBO) are done on the optimized geometries to evaluate the reactivity and stability of the molecules. Electrostatic potential maps offer the charge distribution in these molecules. Time-dependent density functional theory calculations are adopted to construct theoretical absorption spectra in the solvent phase which is compared with the experiments. In addition, the synthesized compounds were studied for their optical properties in solution and solid phases. Consequently, the fluorophores studied, show emissions, which cover a spectral range, going from 416 nm for compound 4b to 418 nm for 4c and 421nm for compound 4a.
Bis-enaminone 3 was coupled with aryldiazonium chlorides 4a, 4b to afford the bis-arylhydrazonopropanals 6a, 6b. Compounds 6a, 6b could be utilized for the synthesis of a variety of bis-(dimethyl 2,3-dihydropyridazine-3,4-dicarboxylate), bis-(pyridazin-3(2H)-one), bis-(2,3-dihydropyridazine-4-carbonitrile) and bis-(3-imino-2,3-dihydropyridazine) derivatives, under ultrasonic irradiation. A comparative study of aforementioned reactions was carried out under conventional method as well as under ultrasonic irradiation conditions.
Recent studies have centred on 1,2-diazines derivatives, which proved to be invaluable materials in the fields of medicine, opto-electronics and agriculture. 1,2-diazines were found to have pharmaceutical applications including a wide range of biological activities, such as antiviral and anticancer, antituberculosis, antimicrobials, antifungus, anti-inflammatory, antihypertensive, diuretics, antithrombics, anticoagulants, antidepressant, anxiolytics, anticonvulsant, analgesic, and anti-multiple sclerosis. Their applications in the field of electronics are mainly focused on highly fluorescent derivatives (with potential as sensors and biosensors, electroluminescent materials, lasers, and other semiconductor devices) and compounds with liquid crystal properties. Herbicidal activity and the grow up factor for plants are also reviewed. Microwave assisted organic synthesis (MAOS) has during the last years become an invaluable tool within chemistry research, which has shown to be a very efficient way towards the synthesis of many compounds. In this review, microwave assisted reactions of 1,2-diazine derivatives have been discussed, outlining an introduction to MW chemistry, N-alkylations, dipolar cycloadditions, cyclocondensations, transition-metal catalysed reactions, and nucleophilic substitution of 1,2- diazines.
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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.
Efficient palladium-catalyzed borylation of protected l-tyrosine triflate with pinacolborane was achieved despite previous reports to the contrary. In addition to the use of an inexpensive boron source, the reaction was carried out in the presence of only 0.5mol% palladium catalyst. Furthermore, the borylation can be performed using pinacolborane prepared in situ from pinacol and borane–diethylaniline complex. This represents a practical entry to 4-borono-l-phenylalanine (l-BPA) derivatives.
A series of (S)-2-(2-(diethylamino)-5-(N-alkyl-N-sulfonamido)pyrimidin-4-ylamino)-3-(4-(carbamoyloxy)phenyl)propanoic acid is discovered as orally available VLA-4 antagonists. Representative compounds 11b and 11p showed efficacy in multiple in vivo animal models. The in vitro selectivity of 11p is also described.
In the last years, the development of small molecule antagonists of VLA-4 for the treatment of diseases, where cell trafficking and activation are important, has increased considerably. Among them, the MK-0617 ligand has proven to be a highly potent and orally active α4β1 antagonist. However, the binding mode of this ligand in the integrin binding site remains unknown. Herein we report a thermodynamic analysis of the interaction between MK-0617 (and one of its isomers) and the VLA-4 protein using molecular docking and the free energy perturbation calculations, based on a comparative model of the α4β1 receptor. Initial complex coordinates were taken from molecular docking assays and submitted to alchemical transformations. Free energy of binding ΔΔG values, derived from experimental IC50 values, were taken as a parameter for determining the most likely binding mode. In addition, molecular dynamics simulations of these ligands within the α4β1 binding site were carried out to elucidate the binding energy profile and identify the most significant residues. Our results indicate that MK-0617 fits within the binding site in a stretched conformation, pointing the carboxylate group towards the MIDAS ion. We observe that, despite the fact that the main contribution to the energetic binding process is due to the electrostatic ion contribution, the nonpolar contribution is not negligible. Additionally, a network of hydrogen bonds participate in stabilizing the ligand-receptor interaction.
N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives of type 4 were designed to replace the 2,6-dichlorobenzoylamine portion of compound 1 in order to identify novel compounds with improved potency against α4-integrins. Several derivatives were identified as very potent dual-acting α4-integrin, α4β1 and α4β7 antagonists. Investigation of a limited number of prodrug esters led to the discovery of the ethyl ester prodrug 42, which demonstrated good intestinal fluid stability and good permeability. Despite low solubility, 42 gave acceptable blood levels of 30 when dosed orally in non-human primates. Additionally, 42 had an overall excellent profile and was selected for clinical trials. Investigation of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives led to the discovery of several very potent dual-acting α4-integrin antagonists. Ethyl ester prodrug 42 advanced to human clinical trials based on the excellent intestinal fluid stability, good permeability and superior efficacy in non-human primates.
From a series of N-acyl 4-(3-pyridonyl)phenylalanine derivatives of 4, the trifluoromethyl derivative 28 was identified as a potent, dual acting alpha4 integrin antagonist with activity in primate models of allergic asthma. Investigation of a series of prodrug esters led to the discovery of the morpholinopropyl derivative 48 that demonstrated good intestinal fluid stability, solubility and permeability. Compound 48 gave high blood levels of 28 when dosed orally in cynomolgus monkeys. Surprisingly, hydrolysis of 48 was rapid in liver microsomes from the pharmacological species, mouse, rat and monkey, but slow in dog and human; in vivo studies also indicated there was prolonged exposure to unchanged prodrug in dogs.
A novel method for the synthesis of 2-phenyl-5-(o-hydroxyphenyl)-pyridazin-3(2H)-ones and 5-(o-hydroxyphenyl)-pyridazin-3(2H)-ones has been found during the reaction of 4-bromomethylcoumarins with phenylhydrazine and hydrazinehydrate, respectively, under controlled alkaline conditions.
Background: Together with β2 integrins and selectins, α4 integrins mediate lymphocyte arrest, extravasation and migration to sites of inflammation. They have been validated as therapeutic targets for inflammatory diseases and, in addition to the marketed anti-α4 antibody natalizumab, numerous small-molecule antagonists have been discovered as candidate drugs. Objective: The present review summarizes work establishing natalizumab as an agent for the treatment of multiple sclerosis and Crohn's disease as well as the safety concerns caused by the development of progressive multifocal leukoencephalopathy in three patients during natalizumab trials. Early development of small-molecule α4 integrin antagonists was limited by their characteristic poor pharmacokinetic properties, but the new generations of compounds discussed in this manuscript have successfully addressed this issue and several are currently in clinical trial for multiple sclerosis. Methods: A Scifinder search of the Chemistry Abstracts database from 2003 to 2008 was augmented by a search of the Investigational Drugs Database (IDDB). Results: Although safety concerns and pharmacokinetic issues have caused many companies to discontinue with this area of research, a number of companies continue to pursue this target. Structures and selected data, where available, for compounds reported since the beginning of 2003 are highlighted in this review.
We report a 3D QSAR study of almost 300 structurally diverse small molecule antagonists of the integrin α4β1 whose biological activity spans six orders of magnitude. The alignment of the molecules was based on the conformation of a structurally related ligand bound to the αIIBβ3 and αvβ3 integrins in X-ray crystallographic studies. The molecular field method, CoMSIA, was used to generate the 3D QSAR models. The resulting models showed that the lipophilic properties were the most important, with hydrogen bond donor and steric properties less relevant. The models were highly significant (r(2)=0.89, q2(LOO)=0.67, r(2) (test set)=0.76), and could make robust predictions of the data (SEE=0.46, SEP=0.78, SEP (test set)=0.66). We predicted the antagonist activities of a further ten compounds with useful accuracy. The model appears capable of predicting α4β1 integrin antagonist activity to within a factor of five for compounds within its domain of applicability. The implications for design of improved integrin antagonists will be discussed.
The integrins are a large family of cell adhesion molecules that are essential for the regulation of cell growth and function. The identification of key roles for integrins in a diverse range of diseases, including cancer, infection, thrombosis and autoimmune disorders, has revealed their substantial potential as therapeutic targets. However, so far, pharmacological inhibitors for only three integrins have received marketing approval. This article discusses the structure and function of integrins, their roles in disease and the chequered history of the approved integrin antagonists. Recent advances in the understanding of integrin function, ligand interaction and signalling pathways suggest novel strategies for inhibiting integrin function that could help harness their full potential as therapeutic targets.
The complex and widespread family of integrin receptors is involved in numerous physiological processes, such as tissue remodeling, angiogenesis, development of the immune response and homeostasis. In addition, their key role has been elucidated in important pathological disorders such as cancer, cardiovascular diseases, osteoporosis, autoimmune and inflammatory diseases and in the pathogenesis of infectious diseases, making them highly important targets for modern drug design campaigns. In this review we seek to present a concise overview of the small molecule antagonists of this diverse and highly complex receptor family. Integrin antagonists are classified according to the targeted integrin receptor and are discussed in four sections. First we present the fibrinogen alpha(IIb)beta3 and the vitronectin alpha (V)beta(3) receptor antagonists. The remaining selective integrin antagonists are examined in the third section. The final section is dedicated to molecules with dual or multiple integrin activity. In addition, the use of antibodies and peptidomimetic approaches to modulate the integrin receptors are discussed, as well providing the reader with an overall appreciation of the field.
A new series of 2,6-quinolinyl derivatives was prepared leading to potent low nanomolar VLA-4/VCAM-1 antagonists.
Suzuki coupling of 4,5-dichloropyridazinone with phenylboronic acid yielded the desired 4-chloro-5-phenylpyridazinone along with 4-aryl and 4,5-diaryl derivatives. An extensive microwave-assisted screen led to the identification of Pd(PEt 3) 2Cl 2 as an ideal catalyst with superior rate and selectivity. Further optimizations provided an effective, regioselective and chemoselective arylation method at room temperature.
N-(3,5-Dichlorophenylsulfonyl)-(R)-thioprolyl biarylalanine 10a has been identified as a potent and specific antagonist of the α4β1 integrin. Altering the configuration of thioproline from R to S led to a series of dual antagonists of α4β1 and α4β7, and the N-acetyl analogue 8b was found to be the most potent dual antagonist. A binding site model for α4β1 and α4β7 is proposed to explain the structure–activity relationship.
The accumulation of leukocytes in various tissues contributes to the pathogenesis of numerous human autoimmune diseases. The integrin α4β7, expressed on the surface of B and T lymphocytes, plays an essential role in lymphocyte trafficking throughout the gastrointestinal (GI) tract via interaction with its primary ligand, mucosal addressin cell adhesion molecule (MAdCAM). Elevated MAdCAM expression in the intestines and liver has been linked to GI-associated autoimmune disorders, including Crohn's disease, ulcerative colitis, and hepatitis C. Monoclonal antibodies that block the interaction of α4β7 with MAdCAM inhibit lymphocyte homing to murine intestines without effecting migration to peripheral organs; this suggests that α4β7-selective antagonists might be useful as GI specific antiinflammatory agents. Here, we report the discovery of highly potent and selective α4β7 antagonists affinity selected from a random peptide-phage library. Subsequent optimization of initial peptide leads afforded α4β7-selective heptapeptide inhibitors that competitively inhibit binding to MAdCAM in vitro and inhibit lymphocyte homing to murine intestines in vivo. Substitution of a single carboxylate moiety alters selectivity for α4β7 by more than 500-fold to afford a potent and selective α4β1 antagonist. The antagonists described here are the first peptides to demonstrate potency and selectivity for α4β7 compared to other integrins.
Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.
alpha(4)beta(1) and alpha(4)beta(7) integrins are key regulators of physiologic and pathologic responses in inflammation and autoimmune disease. The effectiveness of anti-integrin antibodies to attenuate a number of inflammatory/immune conditions provides a strong rationale to target integrins for drug development. Important advances have been made in identifying potent and selective candidates, peptides and peptidomimetics, for further development. Herein, we report the discovery of a series of novel N-benzoyl-L-biphenylalanine derivatives that are potent inhibitors of alpha4 integrins. The potency of the initial lead compound (1: IC(50) alpha(4)beta(7)/alpha(4)beta(1)=5/33 microM) was optimized via sequential manipulation of substituents to generate low nM, orally bioavailable dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. The SAR also led to the identification of several subnanomolar antagonists (134, 142, and 143). Compound 81 (TR-14035; IC(50) alpha(4)beta(7)/alpha(4)beta(1)=7/87 nM) has completed Phase I studies in Europe. The synthesis, SAR and biological evaluation of these compounds are described.
A series of substituted tetrahydrofuroyl-1-phenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. Substitution of the alpha carbon of the tetrahydrofuran with aryl groups increased the specificity for VLA-4 versus alpha(4)beta(7) while amide substitution increased the potency of the series without increasing the specificity. Substitution of the beta carbon of the tetrahydrofuran with keto or amino groups slightly improved the specificity for VLA-4 versus alpha(4)beta(7) but with a significant loss in binding affinity for VLA-4.
Given the proposed involvement of VLA-4 in inflammatory processes, a program to identify orally active VLA-4 antagonists was initiated. Herein, we report the discovery of a N-tetrahydrofuroyl-(L)-phenylalanine derivative (17) and related analogues as potent VLA-4 antagonists with good oral bioavailability.
The accumulation of leukocytes in various organs contributes to the pathogenesis of a number of human autoimmune diseases such as asthma, rheumatoid arthritis, Crohn s disease, ulcerative colitis, hepatitis C, and multiple sclerosis. The inflammatory processes leading to tissue damage and disease are mediated in part by the alpha4 integrins, alpha4beta1 and alpha4beta7, expressed on the leukocyte cell surface. These glycoprotein receptors modulate cell adhesion via interaction with their primary ligands, vascular cell adhesion molecule (VCAM) and mucosal addressin cell adhesion molecule (MAdCAM), expressed in the affected tissue. Upon binding, the combined integrin/CAM interactions at the cell surface result in firm adhesion of the leukocyte to the vessel wall followed by entry into the affected tissue. Elevated cell adhesion molecule (CAM) expression in various organs has been linked with several autoimmune diseases. Monoclonal antibodies specific for alpha4 integrins or their CAM ligands can moderate inflammation in animal models suggesting such inhibitors may be useful for treating human inflammatory diseases. The alpha4 integrins have become well validated drug targets for pharmaceutical companies and numerous publications describing alpha4 integrin antagonists have recently appeared. This article discusses the rationale for targeting alpha4 integrins for the treatment of autoimmune disorders and reviews some currently known antagonists. The methods used to identify lead molecules and the progress of selected antagonists toward becoming new drugs will is also discussed. (131 references).
The design, synthesis, and biological evaluation of N-arylprolyl-dipeptide derivatives as small molecule VLA-4 antagonists is described. Potency against VLA-4 and alpha(4)beta(7) and rat pharmacokinetic evaluation revealed some advantages over the related N-(arylsulfonyl)-prolyl-dipeptide analogues.
A series of potent N-(aralkyl-, arylcycloalkyl-, and heteroaryl-acyl)-4-biphenylalanine VLA-4 antagonists was prepared by rapid analogue methods using solid-phase chemistry. Further optimization led to several highly potent compounds (IC(50) <1 nM). Evaluation of rat pharmacokinetic revealed generally high clearance.
In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis.
In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being.
There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram).
In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.
[formula: see text] 4-Aryl phenylalanines were prepared as free amino acids from the Suzuki coupling of 4-borono phenylalanine with aryl halides in high yields within 5-10 min under microwave irradiation.
Circulating lymphocytes normally migrate through extravascular spaces in relatively low numbers as important members of the immunosurveillance process. That is until signals are received by endothelial cells that there is an underlying infection or inflammatory condition. These vascular surface cells in turn overexpress and present ligands to circulating lymphocyte adhesion molecules. Upon encountering this higher density of ligands, lymphocytes, which had been leisurely rolling along the vascular surface, now become more firmly attached, change shape, and migrate through tight junctions to the sites of infection or inflammation. If the initiating events are not resolved and the condition becomes chronic, there can be a sustained extravasation of lymphocytes that can exacerbate the inflammatory condition, which in turn will continue to recruit more inflammatory cells resulting in unwanted tissue destruction. It is for the attenuation of this cycle of sustained inflammatory cell recruitment that very late activating antigen-4 (VLA-4) antagonists are being developed. Most lymphocytes, except neutrophils, express VLA-4 on their surface and they interact with endothelial vascular cell adhesion molecule-1 (VCAM-1). It is this interaction that VLA-4 antagonists are intended to disrupt, thus, putting an end to the cycle of chronic inflammation, which is the hallmark of many diseases. This review will provide an update of VLA-4 antagonists that have appeared since early 2001 and will discuss some of the issues, both positive and negative, that may be encountered in their development.
The SAR of 1-sulfonyl-cyclopentyl carboxylic acid amides, ligands for the VLA-4 integrin, was investigated. This effort resulted in the identification of N-(3-phenylsulfonyl-3-piperidinoyl)-(L)-4-(2',6'-dimethoxyphenyl)phenylalanine 52 as a potent, selective VLA-4 antagonist (IC(50)=90 pM). Expansion of the SAR demonstrated that this structural unit can be used to identify a diverse series of sub-nanomolar antagonists.
A series of N-carboxy, N-alkyl, and N-carboxamido azabicyclo[2.2.2]octane carboxamides were prepared and assayed for inhibition of alpha4beta1-VCAM-1 and alpha4beta7-MAdCAM-1 interactions. Potency and alpha4beta1/alpha4beta7 selectivity were sensitive to the substituent R1-R3 in the structures 6, 7, and 8. Several compounds demonstrated low nanomolar balanced alpha4beta1/alpha4beta7 in vitro activity. Two compounds were selected for in vivo leukocytosis studies and demonstrated increases in circulating lymphocytes up to 250% over control.
A novel series of pyridazinone-functionalized phenylalanine analogues was prepared and evaluated for inhibition of cellular adhesion mediated by alpha4beta1/VCAM-1 and alpha4beta7/MAdCAM-1 interactions. Concise syntheses were developed and applied for exploration of structure-activity relationships pertaining to the pyridazinone ring as well as the N-acyl phenylalanine scaffold. Potent dual antagonists of alpha4beta1 and alpha4beta7 were generated from an amide subseries; antagonists selective for alpha4beta7 were identified from urea and carbamate-based subseries. The pharmacokinetic properties of selected members of the series have been determined in rats and demonstrate that the use of ester prodrugs and alterations to the amide linkage can lead to improved oral bioavailability in this series. An alpha4beta7-selective member of the carbamate subseries (36c), upon oral administration, demonstrated in vivo efficacy in the mouse DSS colitis model.
Inhibition of leucocyte trafficking by antagonism of the alpha4 (alpha4)-integrin has now been validated as a therapeutic approach for the treatment of inflammatory diseases such as multiple sclerosis (MS) and inflammatory bowel disease (IBD). This validation has been overshadowed by three incidences of progressive multifocal leucoencaphalopathy (PML) in patients receiving natalizumab (Tysabri), a therapeutic monoclonal IgG antibody directed against alpha4-integrins. This led to the initial removal of natalizumab from the market. Following a safety review, it was reintroduced for the treatment of relapsing-remitting MS patients (with restrictions). This has led to a refocus on alpha4-integrins as a therapeutic target across the pharmaceutical industry. Recent advances in small molecule development are worth reviewing. New understanding of pharmacokinetics and selectivity will potentially contribute to the development of alpha4 antagonist with greater clinical efficacy and safety.