ABSTRACT
An improved scale-up synthesis was required for the alpha(V)beta(3)/alpha(V)beta(5) integrin antagonist 1, which had demonstrated oral efficacy in eye disease models of angiogenesis and vascular permeability. A stereodefined, quinoline-substituted, unsaturated ester was conveniently prepared by a Suzuki-Miyaura coupling to facilitate exploration of multiple methods of asymmetric reduction. The catalytic chiral hydrogenation of the corresponding unsaturated acid (Z-5b) with a ruthenium-based metal precursor and the (R)-XylPhanePhos ligand proved particularly efficient and economical. The resulting (3S)-quinoline-containing intermediate was reduced to an equal mixture of tetrahydroquinoline diastereomers. The undesired diastereomer could be recycled to the desired one by an oxidation/reduction protocol. The absolute stereochemistry of 1 was established as 3S,3'S by a combination of X-ray diffraction and chemical means.
Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Integrins/antagonists & inhibitors , Naphthyridines/chemical synthesis , Quinolines/chemical synthesis , Receptors, Vitronectin/antagonists & inhibitors , Naphthyridines/chemistry , Naphthyridines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Stereoisomerism , X-Ray DiffractionABSTRACT
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.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Integrins/antagonists & inhibitors , Phenylalanine/analogs & derivatives , Pyridazines/chemical synthesis , Animals , Biological Availability , Cell Adhesion/drug effects , Cell Adhesion Molecules , Colitis/chemically induced , Colitis/drug therapy , Dextran Sulfate , Endothelial Cells/drug effects , Endothelial Cells/physiology , Esters/chemical synthesis , Esters/chemistry , Esters/pharmacology , Granulocytes/drug effects , Granulocytes/physiology , Humans , Immunoglobulins/metabolism , In Vitro Techniques , Integrin alpha4beta1/metabolism , Integrins/metabolism , K562 Cells , Lymphocytes/drug effects , Lymphocytes/physiology , Mice , Monocytes/drug effects , Monocytes/physiology , Mucoproteins/metabolism , Phenylalanine/chemical synthesis , Phenylalanine/chemistry , Phenylalanine/pharmacology , Prodrugs/chemical synthesis , Prodrugs/chemistry , Prodrugs/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacology , Rats , Structure-Activity Relationship , Umbilical Veins/cytology , Vascular Cell Adhesion Molecule-1/metabolismABSTRACT
The alpha4beta1 integrin, expressed on eosinophils and neutrophils, induces inflammation in the lung by facilitating cellular infiltration and activation. From a number of potent alpha4beta1 antagonists that we evaluated for safety and efficacy, 1 was selected as a lead candidate for anti-asthma therapy by the inhalation route. We devised an optimized stereoselective synthesis to facilitate the preparation of a sufficiently large quantity of 1 for assessment in vivo. Administration of 1 to allergen-sensitive sheep by inhalation blocked the late-phase response of asthma and abolished airway hyper-responsiveness at 24h following the antigen challenge. Additionally, the recruitment of inflammatory cells into the lungs was inhibited. Administration of 1 to ovalbumin-sensitized guinea pigs intraperitoneally blocked airway resistance and inhibited the recruitment of inflammatory cells.
