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.     

Discovery of a potent, orally bioavailable pyrimidine VLA-4 antagonist effective in a sheep asthma model

A series of N-(pyrimidin-4-yl)-phenylalanine VLA-4 antagonists is described. Optimization of substituents at the 2 and 5 positions of the pyrimidine ring gave 14, a very potent VLA-4 inhibitor which is orally active in a sheep asthma model.     

Triamino pyrimidines and pyridines as histamine H(4) receptor modulators

Two series of triamino pyrimidines and a series of triamino pyridines have been synthesized and their structure-activity relationships evaluated for activity at the H₄ receptor in competitive binding and functional assays. Small structural changes in these three hetereoaromatic cores influenced the functional activity of these compounds.     

N-aryl-prolyl-dipeptides as potent antagonists of VLA-4

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.     

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.     

N-Aroyl-L-phenylalanine derivatives as VCAM/VLA-4 antagonists

A series of N-benzoyl-4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine derivatives was prepared in order to optimize the substitution on the N-benzoyl moiety for VCAM/VLA-4 antagonist activity. Disubstitution in the 2- and 6-positions is favored and a range of small alkyl and halogen are tolerated. A model of the bioactive conformation of these compounds is proposed.     

N-benzylpyroglutamyl-L-phenylalanine derivatives as VCAM/VLA-4 antagonists

A series of N-(N-benzylpyroglutamyl)-4-substituted-L-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. Analogues substituted by electron deficient benzoylamino groups bearing bulky ortho substituents had low-nM potency in an ELISA assay and low-microM activity in a cell based assay.     

N-Cycloalkanoyl-L-phenylalanine derivatives as VCAM/VLA-4 antagonists

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 (-) bioactive conformation.     

N-aryl 2,6-dimethoxybiphenylalanine analogues as VLA-4 antagonists

A series of N-arylated phenylalanine derivatives has been synthesized and has been shown to be potent inhibitors of the integrin VLA-4. N-phenyl and N-heteroaryl derivatives with hydrogen bond acceptors in the meta position demonstrated low nanomolar activity against VLA-4.     

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.     

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.     

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.     

Squaric acid derivatives as VLA-4 integrin antagonists

SAR studies aimed at improving the rate of clearance by the incorporation of a 3,4-diamino-3-cyclobutene-1,2-dione group as an amino acid isostere in a series of VLA-4 integrin antagonists are described.     

Expression and pathogenesis of VCAM-1 and VLA-4 cytokines in multiple myeloma

ObjectiveThe objective of this study is to investigate the expression of Vascular cell adhesion molecule-1 (VCAM-1) and very late appearing antigen-4 (VLA-4) cytokines in MM (multiple Myeloma).MethodForty patients with MM are selected as the experimental group and 30 healthy persons as the control group. Flow cytometry is used to detect the expression of VCAM-1 (CD106), VLA-4 (CD49d), CD38 and CD138 antigens in experimental group and control group. ELISA (Enzyme Linked Immunosorbent Assay) is used to detect the concentration of VCAM-1 in serum of experimental group and control group. RT-PCR is used to detect the expression of VCAM-1.ResultsThe positive rate and antigen expression rate of VACM-1 antigen in the experimental group were significantly higher than those in the control group (P < 0.05). There were statistical differences of VLA-4 and VCAM-1 antigens between the initial diagnosis group and the relapse/refractory group, and between the relapse/refractory group and the platform stage group (P < 0.05). There were significant differences between VLA-4 antigen and VACM-1 antigen, phase I and phase II, and between phase I and phase III (P < 0.05). The concentration of VCAM-1 and the expression of VCAM-1 mRNA in the experimental group were significantly higher than (P < 0.01). In the different stages of ISS (International Staging System) and different disease groups in the experimental group, the concentration of VCAM-1 and the expression level of VCAM-1 mRNA are significantly different among the three groups of stage I, II and III (P < 0.01). There is a significant difference between the initial diagnosis group, the relapse/refractory group and the platform group (P < 0.05).ConclusionThere are abnormal expressions of adhesion molecules VCAM-1 and VLA-4 in multiple myeloma patients, which are related to ISS staging.     

Amidines as amide bond replacements in VLA-4 antagonists

VLA-4 (alpha(4)beta(1), very late activating antigen-4), a key cell surface integrin plays an important role in inflammation by promoting leukocyte attachment and extravasation from the vasculature into the peripheral tissues. As such, VLA-4 antagonists may be useful in the treatment, prevention, and suppression of diseases where cell adhesion and migration are important such as asthma, rheumatoid arthritis, and multiple sclerosis. Herein, we report on the discovery, synthesis, and biological evaluation of amidines as small molecule antagonists of VLA-4.     

Different embryo-fetal toxicity effects for three VLA-4 antagonists

BACKGROUND: VLA‐4 (Very late antigen 4, integrin α₄β₁) plays an important role in cell‐cell interactions that are critical for development. Homozygous null knockouts of the α₄subunit of VLA‐4 or VCAM‐1 (cell surface ligand to VLA‐4) in mice result in abnormal placental and cardiac development and embryo lethality. Objectives of the current study were to assess and compare the teratogenic potential of three VLA‐4 antagonists. METHODS: IVL745, HMR1031, and IVL984 were each evaluated by the subcutaneous route in standard embryo‐fetal developmental toxicity studies in rats and rabbits. IVL984 was also evaluated in mice. Fetuses were examined externally, viscerally, and skeletally. RESULTS: IVL745 did not cause significant maternal or fetal effects at doses up to 100 or 250 mg/kg/day in rats or rabbits, respectively. HMR1031 treatment resulted in marked maternal toxicity and slight fetal toxicity at the highest tested doses of 200 and 75 mg/kg/day in rats and rabbits, respectively. HMR1031 embryo‐fetal effects consisted of slightly lower body weight and crown‐rump length in rats and minor sternebral defects in rabbits. IVL984 treatment resulted in minimal maternal effects at doses up to 40, 15, and 100 mg/kg/day in rats, rabbits, and mice, respectively (excluding abortions in rabbits). However, marked developmental effects were observed at the lowest tested IVL984 doses, 1, 0.2, and 3 mg/kg/day in rats, rabbits, and mice, respectively. IVL984 embryo‐fetal effects consisted of increased total post‐implantation loss due to early resorptions and high incidences of cardiac malformations and skeletal malformations and/or variations. Notably, spiral septal defects were observed in up to 76% of rat fetuses and up to 58% of rabbit fetuses. CONCLUSIONS: Dramatic differences in teratogenic potential were observed: IVL745 was not teratogenic, HMR1031 caused slight embryo‐fetal effects at maternally‐toxic doses, and IVL984 was a potent teratogen at doses where direct maternal toxicity was limited to abortions in rabbits. Prominent effects of IVL984 included embryo lethality and cardiac malformations including spiral septal defects in three species. Birth Defects Res B 71:55–68, 2004. © 2004 Wiley‐Liss, Inc.     

Pyridone derivatives as potent and selective VLA-4 integrin antagonists

A novel series of pyridone inhibitors has been identified through pharmacophore analysis, as potent antagonists of VLA-4.     

The discovery of sulfonylated dipeptides as potent VLA-4 antagonists

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.     

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.     

N-acyl phenylalanine analogues as potent small molecule VLA-4 antagonists

We have identified a series of low molecular weight (Mr < 500) N-acylphenylalanines that are effective inhibitors of the VCAM-VLA-4 interaction. Investigation of the SAR of the N-acyl moiety led to the identification of N-benzylpyroglutamyl derivatives as being particularly potent.