ABSTRACT
A hit-to-lead optimization process was carried out on the high throughput screening hit compound 1 resulting in the identification of several potent and selective CCR1 receptor antagonists. Compound 37 shows the best overall profile with IC(50) values of <100 nM in binding and functional assays.
Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Receptors, CCR1/antagonists & inhibitors , Calcium/metabolism , Cell Line , Cell Movement/drug effects , Chemokine CCL3/metabolism , Chemotaxis/drug effects , Humans , Molecular Structure , Monocytes/cytology , Monocytes/drug effects , Monocytes/metabolism , Piperidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
Synthesis and structure-activity relationship of a series of 4-(2-aryl-cyclopropylamino)-quinoline-3-carbonitrile derivatives as EGFR inhibitors is described. Compounds 29 and 30 showed potent in vitro inhibitory activity in the enzymatic assay as well as in the functional cellular assay. They are moderately selective against other types of tyrosine kinases.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , ErbB Receptors/antagonists & inhibitors , Nitriles/chemistry , Nitriles/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Enzyme Inhibitors/chemical synthesis , Nitriles/chemical synthesis , Quinolines/chemical synthesis , Structure-Activity RelationshipABSTRACT
Structure-activity relationship studies on a series of Boc-indole derivatives as LXR agonists are described. Compound 1 was identified as an LXR agonist through structure-based virtual screening followed by high-throughput gene profiling. Replacement of the indan linker portion in 1 with an open-chain linker resulted in compounds with similar or improved in vitro potency and cellular functional activity. The Boc group at the N-1 position of the indole moiety can be replaced with a benzoyl group. The SAR studies led to the identification of compound 8, a potent LXRbeta agonist with an EC50 of 12 nM in the cofactor recruitment assay.
Subject(s)
DNA-Binding Proteins/agonists , Indoles/chemistry , Indoles/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Binding Sites , Cell Line , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Liver X Receptors , Models, Molecular , Molecular Structure , Orphan Nuclear Receptors , Sterol Regulatory Element Binding Protein 1/genetics , Sterol Regulatory Element Binding Protein 1/metabolism , Structure-Activity Relationship , Up-RegulationABSTRACT
A structurally novel liver X receptor (LXR) agonist (1) was identified from internal compound collection utilizing the combination of structure-based virtual screening and high-throughput gene profiling. Compound 1 increased ABCA1 gene expression by eightfold and SREBP1c by threefold in differentiated THP-1 macrophage cell lines. Confirmation of its agonistic activity against LXR was obtained in the co-factor recruitment and reporter transactivation assays. Structure-activity relationship studies on compound 1 are described.
Subject(s)
DNA-Binding Proteins/agonists , Gene Expression Regulation/drug effects , Indoles/pharmacology , Macrophages/drug effects , Monocytes/drug effects , Receptors, Cytoplasmic and Nuclear/agonists , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Cell Line , Gene Expression Regulation/physiology , Humans , Indoles/chemical synthesis , Liver X Receptors , Macrophages/metabolism , Models, Chemical , Monocytes/cytology , Orphan Nuclear Receptors , Sterol Regulatory Element Binding Protein 1/genetics , Sterol Regulatory Element Binding Protein 1/metabolism , Structure-Activity RelationshipABSTRACT
Design and synthesis of a series of 3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenylamino)cyclobutenedione derivatives as novel CCR1 antagonists are described. Structure-activity relationship studies led to the identification of compound 22, which demonstrated potent binding activity, functional antagonism of CCR1 as well as good species cross-reactivity. In addition, compound 22 also showed desirable pharmacokinetic profiles and was selected for in vivo studies in the mouse collagen-induced arthritis model.
Subject(s)
Arthritis, Experimental/drug therapy , Benzyl Compounds/pharmacology , Cyclobutanes/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Administration, Oral , Animals , Arthritis, Experimental/chemically induced , Benzyl Compounds/chemistry , Binding Sites , Collagen , Cyclobutanes/chemistry , Disease Models, Animal , Drug Design , Male , Mice , Mice, Inbred BALB C , Receptors, CCR1 , Structure-Activity RelationshipABSTRACT
alpha(4)beta(1) and alpha(4)beta(7) integrins are key regulators of physiologic and pathologic responses in inflammation and autoimmune disease. The effectiveness of anti-integrin antibodies to attenuate a number of inflammatory/immune conditions provides a strong rationale to target integrins for drug development. Important advances have been made in identifying potent and selective candidates, peptides and peptidomimetics, for further development. Herein, we report the discovery of a series of novel N-benzoyl-L-biphenylalanine derivatives that are potent inhibitors of alpha4 integrins. The potency of the initial lead compound (1: IC(50) alpha(4)beta(7)/alpha(4)beta(1)=5/33 microM) was optimized via sequential manipulation of substituents to generate low nM, orally bioavailable dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. The SAR also led to the identification of several subnanomolar antagonists (134, 142, and 143). Compound 81 (TR-14035; IC(50) alpha(4)beta(7)/alpha(4)beta(1)=7/87 nM) has completed Phase I studies in Europe. The synthesis, SAR and biological evaluation of these compounds are described.