Identification of novel series of human CCR1 antagonists.

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.

Synthesis and structure-activity relationship of 4-(2-aryl-cyclopropylamino)-quinoline-3-carbonitriles as EGFR tyrosine kinase inhibitors.

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.

2-Aryl-N-acyl indole derivatives as liver X receptor (LXR) agonists.

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.

Structure-activity relationships of novel, highly potent, selective, and orally active CCR1 antagonists.

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.

Discovery and structure-activity relationship studies of indole derivatives as liver X receptor (LXR) agonists.

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.

Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: discovery of TR-14035, a dual alpha(4)beta(7)/alpha(4)beta(1) integrin antagonist.

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.