Discovery of Small Molecule Drugs Targeting the Biogenesis of microRNA-155 for the Treatment of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that often leads to functional disorder in multiple organs, most often with symptoms related to skin lesions, cardiovascular disease and kidney damage. Although significant efforts have been made to find efficient therapies, it still remains uncured. Furthermore, the current therapy is often associated with adverse side effects and leads to a high economic burden for society.

Verification of the Major Metabolic Oxidation Path for the Naphthoyl Group in Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTh2) Antagonist 2-(2-(1-Naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic Acid (Setipiprant/ACT-129968).

Various racemic and enantioenriched (trans)-X,Y-dihydroxy-X,Y-dihydronaphthoyl analogues as well as X-hydroxy-naphthoyl analogues of CRTh2 antagonist 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (1, Setipiprant/ACT-129968) were synthesized in order to gain insight into regio- and enantioselectivity of the metabolic oxidation of 1 and to verify the structures of four metabolites that were proposed earlier in a clinical ADME study. Analytical data of the synthetic standards were compared with data from samples of biological origin. The two major metabolites M7 and M9 were unambiguously verified as 2-(2-((trans)-3,4-dihydroxy-3,4-dihydronaphthalene-1-carbonyl)- and 2-(2-((trans)-5,6-dihydroxy-5,6-dihydronaphthalene-1-carbonyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid, respectively, each composed of two enantiomers with 68% and 44% ee in favor of (+)-(3S,4S)-M7 and (+)-(5S,6S)-M9, respectively.

Identification of 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (setipiprant/ACT-129968), a potent, selective, and orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonist.

Herein we describe the discovery of the novel CRTh2 antagonist 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 28 (setipiprant/ACT-129968), a clinical development candidate for the treatment of asthma and seasonal allergic rhinitis. A lead optimization program was started based on the discovery of the recently disclosed CRTh2 antagonist 2-(2-benzoyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 5. An already favorable and druglike profile could be assessed for lead compound 5.

Evolution of novel tricyclic CRTh2 receptor antagonists from a (E)-2-cyano-3-(1H-indol-3-yl)acrylamide scaffold.

(E)-2-(3-(3-((3-Bromophenyl)amino)-2-cyano-3-oxoprop-1-en-1-yl)-1H-indol-1-yl)acetic acid (1) was discovered in a HTS campaign for CRTh2 receptor antagonists. An SAR around this hit could be established and representatives with interesting activity profiles were obtained. Ring closing tactics to convert this hit series into a novel 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole based CRTh2 receptor antagonist series is presented.

Novel 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl)acetic acids: discovery and hit-to-lead evolution of a selective CRTh2 receptor antagonist chemotype.

Hit-to-lead evolution of 2-(2-((2-(4-chlorophenoxy)ethyl)thio)-1H-benzo[d]imidazol-1-yl)acetic acid (1), discovered in a high-throughput screening campaign as a novel chemotype of CRTh2 receptor antagonist, is presented. SAR development as well as in vitro and in vivo DMPK properties of selected representatives of substituted 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl)acetic acids are discussed.

Protein kinases as targets for anticancer agents: from inhibitors to useful drugs.

Many components of mitogenic signaling pathways in normal and neoplastic cells have been identified, including the large family of protein kinases, which function as components of signal transduction pathways, playing a central role in diverse biological processes, such as control of cell growth, metabolism, differentiation, and apoptosis. The development of selective protein kinase inhibitors that can block or modulate diseases caused by abnormalities in these signaling pathways is widely considered a promising approach for drug development. Because of their deregulation in human cancers, protein kinases, such as Bcr-Abl, those in the epidermal growth factor-receptor (HER) family, the cell cycle regulating kinases such as the cyclin-dependent kinases, as well as the vascular endothelial growth factor-receptor kinases involved in the neo-vascularization of tumors, are among the protein kinases considered as prime targets for the development of selective inhibitors.

Structure-based design and synthesis of 2-benzylidene-benzofuran-3-ones as flavopiridol mimics.

Novel 2-benzylidene-benzofuran-3-ones were designed and synthesized to mimic flavopiridol, a well-established inhibitor of cyclin-dependent kinases (CDKs) which is currently undergoing clinical evaluation. The underlying design concepts as well as the synthesis and structure-activity relationships (CDKs 1, 2, and 4 enzyme assays) of these mimics are described. Inhibitors of CDKs 1 and 2 that are more potent and selective than flavopiridol were obtained.