Discovery of N -{ N -[(3-Cyanophenyl)sulfonyl]-4( R )-cyclobutylamino-( l )-prolyl}-4-[(3′,5′-dichloroisonicotinoyl)amino]-( l )-phenylalanine (MK-0668), an Extremely Potent and Orally Active Antagonist of Very Late Antigen-4 (original) (raw)

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

Bioorganic & Medicinal Chemistry Letters, 2002

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.

N-Tetrahydrofuroyl-( l)-phenylalanine derivatives as potent VLA4 antagonists

Bioorganic & Medicinal Chemistry Letters, 2002

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. #

Heterocycle-substituted proline dipeptides as potent VLA-4 antagonists

Bioorganic & Medicinal Chemistry Letters, 2010

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.

N-(3-Phenylsulfonyl-3-piperidinoyl)-phenylalanine derivatives as potent, selective VLA-4 antagonists

Bioorganic & Medicinal Chemistry Letters, 2003

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 0 ,6 0 -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. #

Highly constrained bicyclic VLA-4 antagonists

Bioorganic & Medicinal Chemistry Letters, 2007

VLA-4 is implicated in several inflammatory and autoimmune disease states. A series of cyclic b-amino acids (b-aa) was studied as VLA-4 antagonists. Binding affinity was highly dependent on the dihedral angle (/) between the amino and the carboxyl termini of the b-aa. Compound 5m where the b-aa is embedded in a bicycle possesses the most preferred / (120°). It is a potent and bioavailable VLA-4 antagonist (VCAM-Ig a4b1 IC 50 = 54 nM, rat po F = 49%).

Influence of acid surrogates toward potency of VLA4 antagonist

Bioorganic & Medicinal Chemistry Letters, 2005

A series of VLA-4 antagonist were synthesized wherein carboxylic acid was replaced by various acid surrogates. The effect of these acid surrogates toward potency was evaluated in a binding assay. A number of acid surrogates were potent antagonist of VLA-4, albeit significantly less potent than the corresponding carboxylic acid. Heterocyclic acid surrogate, oxadiazolidinone 3, demonstrated an improved pharmacokinetic property when dosed intravenously.

Discovery of Very Late Antigen-4 (VLA-4, 4 1 Integrin) Allosteric Antagonists

Journal of Biological Chemistry, 2011

Integrins are cell adhesion receptors that mediate cell-to-cell, or cell-to-extracellular matrix adhesion. They represent an attractive target for treatment of multiple diseases. Two classes of small molecule integrin inhibitors have been developed. Competitive antagonists bind directly to the integrin ligand binding pocket and thus disrupt the ligand-receptor interaction. Allosteric antagonists have been developed primarily for α(L)β(2)- integrin (LFA-1, lymphocyte function-associated antigen-1). Here we present the results of screening the Prestwick Chemical Library using a recently developed assay for the detection of α(4)β(1)-integrin allosteric antagonists. Secondary assays confirmed that the compounds identified: 1) do not behave like competitive (direct) antagonists; 2) decrease ligand binding affinity for VLA-4 ∼2 orders of magnitude; 3) exhibit antagonistic properties at low temperature. In a cell based adhesion assay in vitro, the compounds rapidly disrupted cellular aggregates. In accord with reports that VLA-4 antagonists in vivo induce mobilization of hematopoietic progenitors into the peripheral blood, we found that administration of one of the compounds significantly increased the number of colony-forming units in mice. This effect was comparable to AMD3100, a well known progenitor mobilizing agent. Because all the identified compounds are structurally related, previously used, or currently marketed drugs, this result opens a range of therapeutic possibilities for VLA-4-related pathologies.

N-Cycloalkanoyl-l-Phenylalanine Derivatives as VCAM/VLA-4 Antagonists

Bioorganic & Medicinal Chemistry Letters, 2002

A systematic structure-activity relationship investigation of the lead compound 1 resulted the identification of several N-[(substituted alkyl)cycloalkanoyl]-4-[((2,6-dichlorophenyl)carbonyl)amino]-l-phenylalanine derivatives as potent VCAM/VLA-4 antagonists. The data are consistent with a model of these compounds in which these alkanoylphenylalanines reside in a compact gauche (À) bioactive conformation. #