ABSTRACT
We have investigated the SAR of a series of pyrimidinone-containing Cdc7 kinase inhibitors. A wide range of amine substitutions give potent compounds with activities (K(i)) less than 1nM. Kinase selectivity is reasonable and cytotoxicity corresponds to inhibition of MCM2 phosphorylation.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Amines/chemistry , Amines/pharmacology , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Humans , Minichromosome Maintenance Complex Component 2 , Nuclear Proteins/metabolism , Phosphorylation/drug effects , Protein Serine-Threonine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
Leukotriene B(4) (LTB(4)) is a potent, proinflammatory mediator involved in the pathogenesis of a number of diseases including inflammatory bowel disease, psoriasis, rheumatoid arthritis, and asthma. The enzyme LTA(4) hydrolase represents an attractive target for pharmacological intervention in these disease states, since the action of this enzyme is the rate-limiting step in the production of LTB(4). Our previous efforts focused on the exploration of a series of analogues related to screening hit SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) and resulted in the identification of potent, orally active inhibitors such as 2. Additional structure-activity relationship studies around this structural class resulted in the identification of a series of alpha-, beta-, and gamma-amino acid analogues that are potent inhibitors of the LTA(4) hydrolase enzyme and demonstrated good oral activity in a mouse ex vivo whole blood LTB(4) production assay. The efforts leading to the identification of clinical candidate SC-57461A (8d, 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid) are described.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Epoxide Hydrolases/antagonists & inhibitors , beta-Alanine/chemical synthesis , Administration, Oral , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Leukotriene A4/biosynthesis , Leukotriene A4/blood , Mice , Structure-Activity Relationship , beta-Alanine/analogs & derivatives , beta-Alanine/chemistry , beta-Alanine/pharmacologyABSTRACT
A peptidomimetic inhibitor of the integrin alpha(v)beta(3) has been substantially modified to produce several new nonpeptidic antagonists. These inhibitors are simpler to synthesize and belong to new classes of scaffolds. Some of the compounds served as the initial lead for further optimization, which led to the discovery of potent and selective inhibitors of the integrin alpha(v)beta(3).
Subject(s)
Acetates/chemical synthesis , Integrin alphaVbeta3/antagonists & inhibitors , Propionates/chemical synthesis , Stilbenes/chemical synthesis , Acetates/chemistry , Animals , Humans , Integrin alphaVbeta3/chemistry , Propionates/chemistry , Stilbenes/chemistryABSTRACT
The synthesis and biological evaluation of a series of heterocyclic analogues of the previously reported LTA(4) hydrolase inhibitor 1b are described. Imidazopyridine and purine analogues are specifically highlighted with several demonstrating excellent potency in our in vitro assays, as well as good oral activity in a mouse ex vivo assay.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Epoxide Hydrolases/antagonists & inhibitors , Purines/chemical synthesis , Purines/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Epoxide Hydrolases/blood , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Humans , In Vitro Techniques , Indicators and Reagents , Mice , Recombinant Proteins/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
The synthesis and biological evaluation of a series of functionalized pyrrolidine- and piperidine-containing analogues of our lead LTA(4) hydrolase inhibitor, SC-57461A, is described. A number of compounds showed excellent potency in our in vitro screens and several demonstrated good oral activity in a mouse ex vivo assay. These efforts led to the identification of SC-56938 (14) as a potent, orally active inhibitor of LTA(4) hydrolase.