Potent VLA-4 Antagonists Research Articles

Heterocycle-substituted proline dipeptides as potent VLA-4 antagonists

A variety of N-linked tertiary amines and heteroarylamines were examined at the 4-position of sulfonylated proline dipeptides in order to improve VLA-4 receptor off-rates and overcome the issue of CYP3A4 time-dependent inhibition of ester prodrugs. A tight-binding inhibitor 5j with a long off-rate provided sustained receptor occupancy despite poor oral pharmacokinetics.

A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid

During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-(2-methylphenylamino)benzoxazole moiety which mimics the diphenylurea structure. However, this modification resulted in a significant decrease ( 3, IC 50 = 19 nM) in VLA-4 inhibitory activity compared to 1 (IC 50 = 1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic acid moiety in compound 3. As a result, our efforts have led to the discovery of trans-4-substituted cyclohexanecarboxylic acid derivative 11b (IC 50 = 2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties (CL = 3.3 ml/min/kg, F = 51%) in rats.

Identification of 4-[1-[3-chloro-4-[ N’-(5-fluoro-2-methylphenyl)ureido]phenylacetyl]-(4 S)-fluoro-(2 S)-pyrrolidinylmethoxy]benzoic acid as a potent, orally active VLA-4 antagonist

Optimization of benzoic acid derivatives by introducing substituents into the diphenyl urea moiety led to the identification of compound 20l as a potent VLA-4 antagonist. Compound 20l inhibited eosinophil infiltration into bronchial alveolar lavage fluid in a murine asthma model by oral dosing and its efficacy was comparable to anti-mouse α4 antibody (R1-2). Furthermore, this compound significantly blocked bronchial hyper-responsiveness in the model.

Imidazopyridines as VLA-4 integrin antagonists

We describe a novel series of imidazopyridine substituted phenylalanines which are potent VLA-4 antagonists. A wide variety of substituents are tolerated as replacements for the pendant 3-pyridyl ring. A clear structure–activity relationship was identified around the substitution of the 3-amino-cyclobut-2-enone portion of the molecule.

Effect of enalapril on the in vitro and in vivo peptidyl cleavage of a potent VLA-4 antagonist

BIO1211 is a small peptidyl potent antagonist of the activated form of α4β1 integrin. The effect of enalapril on the in vitro and in vivo cleavage of BIO1211 was investigated. In heparinized blood, plasma and rat liver, lung and intestinal homogenates, BIO1211 was converted rapidly to BIO1588 by hydrolytic cleavage of the terminal dipeptide moiety. This cleavage could be inhibited by EDTA and the ACE inhibitor, enalaprilat, the de-esterified acid derivative of enalapril. Enalaprilat inhibited the hydrolysis of BIO1211 in a concentration-dependent manner with IC50 values of 2 nM in human and sheep plasma and 10 nM in rat plasma. In rat lung homogenate supernatant, the maximum inhibition of the conversion of BIO1211 to BIO1588 was ∼80% at 1 µM with no further effect up to 100 µM of enalaprilat. Following a concomitant IV administration of enalapril and BIO1211 at 3 mg/kg each, the AUC and the half-life values of BIO1211 increased 18- and 10-fold, respectively. The AUC of BIO1588 decreased ∼2-fold with no change in its plasma half-life. When rats were dosed intravenously with enalapril followed by an intratracheal dose of BIO1211, there was ∼2.5-fold decrease in the AUC of BIO1588 and a 2.4-fold increase in its plasma half-life.

Highly constrained bicyclic VLA-4 antagonists

VLA-4 is implicated in several inflammatory and autoimmune disease states. A series of cyclic β-amino acids (β-aa) was studied as VLA-4 antagonists. Binding affinity was highly dependent on the dihedral angle ( ϕ) between the amino and the carboxyl termini of the β-aa. Compound 5m where the β-aa is embedded in a bicycle possesses the most preferred ϕ (120°). It is a potent and bioavailable VLA-4 antagonist (VCAM-Ig α4β1 IC 50 = 54 nM, rat po F = 49%).

2,6-Quinolinyl derivatives as potent VLA-4 antagonists

A new series of 2,6-quinolinyl derivatives was prepared leading to potent low nanomolar VLA-4/VCAM-1 antagonists.

Solid-phase synthesis of 2,3-diphenylpropionic acid library as VLA-4 antagonists

2,3-Diphenylpropionic acid library for VLA-4 antagonist was synthesized on solid-phase. Comparison of the two synthetic routes via an orthogonal generation of two aromatic amino functional groups are discussed. From this work, several compounds were identified as potent VLA-4 antagonists.

2,3‐Diphenylpropionic Acids as Potent VLA‐4 Antagonists

AbstractFor Abstract see ChemInform Abstract in Full Text.

Identified a morpholinyl-4-piperidinylacetic acid derivative as a potent oral active VLA-4 antagonist

An investigation into the structure–activity relationship of a lead compound, prolyl-5-aminopentanoic acid 4, led to the identification of a novel series of 4-piperidinylacetic acid, 1-piperazinylacetic acid, and 4-aminobenzoic acid derivatives as potent VLA-4 antagonists with low nanomolar IC 50 values. A representative compound morpholinyl-4-piperidinylacetic acid derivative ( 13d: IC 50 = 4.4 nM) showed efficacy in the Ascaris-antigen sensitized murine airway inflammation model by oral administration.

2,3-Diphenylpropionic acids as potent VLA-4 antagonists

The discovery and SAR of 2,3-diphenylpropionic acid derivatives as highly potent VLA-4 antagonists are described. One representative compound, 9cc has inhibited intercellular adhesion by a VCAM-1/VLA-4 interaction with an IC 50 of 1.7 nM, and has good pharmacokinetics and oral bioavailability.

Trifluoromethyl-substituted hydantoins, versatile building blocks for rational drug design

Preparatively simple, one-pot syntheses of trifluoromethyl-substituted hydantoins starting from Boc-protected imines of hexafluoroacetone and trifluoropyruvate are described. They represent valuable building blocks for the construction of constrained peptides or as scaffolds for the synthesis of highly potent VLA-4 antagonists.

Bioisosteric replacement of anilide with benzoxazole: potent and orally bioavailable antagonists of VLA-4

We have designed and synthesized a series of heterocyclic bioisosteres for an anilide based on molecular modeling. Excellent potency was retained in the benzoxazole and the benzimidazole derivatives, where a hydrogen bond acceptor is appropriately positioned to mimic the amide bond oxygen. The deletion of the hydrogen bond donor (N–H) led to improved lipophilicity and bioavailability. In the process, 9a was identified as a potent, specific, and bioavailable VLA-4 antagonist, while 9c was found to be a potent and bioavailable dual antagonist of VLA-4 and α4β7.

Dehydrophenylalanine derivatives as VLA-4 integrin antagonists

We describe a series of dehydrophenylalanine derivatives where the Z isomers are potent VLA-4 antagonists but are subject to rapid biliary clearance and the E isomers have poor activity but have a slower rate of clearance. These configurationally constrained molecules have led to the design of a novel class of benzodiazepine VLA-4 antagonists.

Aromatic β-Amino Acids as Asp-Phg Mimics in LDV Derived VLA-4 Antagonists­

Aromatic β-amino acid esters 2a-h were prepared in racemic and enantiomerically pure form by the Radionow reaction or based on the method described by Davis and used as mimics of the Asp-Phg C-terminus in LDV derived VLA-4 antagonists. As a promising β-amino acid ester, 11 was identified and used for the synthesis of the highly potent VLA-4 antagonist S9059 with an IC50 of 1.6 nM in a cell attachment assay.

Substituted 3-amino biaryl propionic acids as potent VLA-4 antagonists

A series of substituted N-(3,5-dichlorobenzenesulfonyl)-( l)-prolyl- and ( l)-azetidyl-β-biaryl β-alanine derivatives was prepared as selective and potent VLA-4 antagonists. The 2,6-dioxygenated biaryl substitution pattern is important for optimizing potency. Oral bioavailability was variable and may be a result of binding to circulating plasma proteins.

N-(Arylacetyl)-biphenylalanines as Potent VLA-4 Antagonists

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.

Substituted tetrahydrofuroyl-1-phenylalanine derivatives as potent and specific VLA-4 antagonists

A series of substituted tetrahydrofuroyl-1-phenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. Substitution of the α carbon of the tetrahydrofuran with aryl groups increased the specificity for VLA-4 versus α 4β 7 while amide substitution increased the potency of the series without increasing the specificity. Substitution of the β carbon of the tetrahydrofuran with keto or amino groups slightly improved the specificity for VLA-4 versus α 4β 7 but with a significant loss in binding affinity for VLA-4.

N-Tetrahydrofuroyl-( l)-phenylalanine derivatives as potent VLA-4 antagonists

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.

Substituted N-(3,5-Dichlorobenzenesulfonyl)- l-prolyl-phenylalanine analogues as potent VLA-4 antagonists

A series of substituted N-(3,5-dichlorobenzenesulfonyl)- l-prolyl- and α-methyl- l-prolyl-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. The compounds showed excellent potency with a wide variety of neutral, polar, electron withdrawing or donating groups on the phenylalanine ring (IC 50∼1 nM). Heteroaryl ring substitution for phenylalanine was also well tolerated. Pharmacokinetic studies in rat were performed on a representative set of compounds in both series.