ABSTRACT
We describe a series of 1,2,4-oxadiazoles, which are potent antagonists of the integrin alpha(v)beta3 and, in addition, show selectivity relative to the other beta3 integrin alpha(IIb)beta3. In whole cells, the majority of these analogs also demonstrated modest selectivity against other alpha(v) integrins such as alpha(v)beta1 and alpha(v)beta6.
Subject(s)
Butyrates/chemical synthesis , Butyrates/pharmacology , Integrin alphaVbeta3/antagonists & inhibitors , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacology , Antigens, Neoplasm , Butyrates/chemistry , Cell Line , Humans , Integrins/antagonists & inhibitors , Molecular Structure , Oxadiazoles/chemistry , Receptors, Vitronectin/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
We describe a series of conformationally-restricted cinnamic acid peptidomimetics as well as several cinnamic acid isosteres, including 3-phenylpropionic acids, 2-amino-3-phenylpropionic acids, phenoxyacetic acids and 2-phenylcyclopropylcarboxylic acids. Several analogues demonstrated low to sub-nanomolar potencies against alpha(v)beta(3) and greater than 200-fold selectivity against the other beta(3) integrin alpha(IIb)beta(3). In whole 293 cells, many of these analogues also showed modest selectivity against other alpha(v) integrins such as alpha(v)beta(1) and alpha(v)beta(5). These compounds were synthesized from readily available starting materials using either Heck or Mitsunobu coupling conditions.
Subject(s)
Cinnamates/chemical synthesis , Cinnamates/metabolism , Integrin alphaVbeta3/antagonists & inhibitors , Integrin alphaVbeta3/metabolism , Humans , StereoisomerismABSTRACT
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.
