Diamine containing VLA-4 antagonists (original) (raw)
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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%).
Bioorganic & Medicinal Chemistry Letters, 2005
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.
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. #
3D QSAR (COMFA) of a series of potent and highly selective VLA4 antagonists
Journal of Computer-aided Molecular Design, 2002
The integrin VLA-4 (α4β1) is involved in the migration of white blood cells to sites of inflammation, and is implicated in the pathology of a variety of diseases including asthma and multiple sclerosis. We report the structure-activity relationships of a series of VLA-4 antagonists that were based upon the integrin-binding sequence of the connecting segment peptide of fibronectin (Leu-Asp-Val), and of VCAM-1 (Ile-Asp-Ser), both natural ligands of VLA-4. We explore variation in the ligand derived peptide portion of these antagonists and also in the novel N-terminal cap, which have discovered through chemical optimization, and which confers high affinity and selectivity. Using the X-ray derived conformation of the Ile-Asp-Ser region of VCAM-1, we rationalize the structure-activity relationships of these antagonists using 3D QSAR (COMFA). The COMFA model was found to be highly predictive with a cross-validated R2 CVof 0.7 and a PRESS of 0.49. The robustness of the model was confirmed by testing the influence of various parameters, including grid size, column filtering, as well as the role of orientation of the aligned molecules. Our results suggest that the VCAM-1 structure is useful in generating highly predictive models of our VLA-4 antagonists. The COMFA model coupled with the knowledge that the peptide amides are tolerant to methylation should prove useful in future peptidomimetic design studies.
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. #
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.