ABSTRACT
Antagonism of CCR9 is a promising mechanism for treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. There is limited experimental data on CCR9 and its ligands, complicating efforts to identify new small molecule antagonists. We present here results of a successful virtual screening and rational hit-to-lead campaign that led to the discovery and initial optimization of novel CCR9 antagonists. This work uses a novel data fusion strategy to integrate the output of multiple computational tools, such as 2D similarity search, shape similarity, pharmacophore searching, and molecular docking, as well as the identification and incorporation of privileged chemokine fragments. The application of various ranking strategies, which combined consensus and parallel selection methods to achieve a balance of enrichment and novelty, resulted in 198 virtual screening hits in total, with an overall hit rate of 18%. Several hits were developed into early leads through targeted synthesis and purchase of analogs.
Subject(s)
Computer Simulation , Molecular Docking Simulation/methods , Receptors, CCR/agonists , Drug Discovery/methods , Drug Evaluation, Preclinical/methods , High-Throughput Screening Assays/methods , Ligands , Molecular Structure , Principal Component Analysis , Receptors, CXCR4/agonists , Receptors, G-Protein-Coupled/metabolism , Structure-Activity RelationshipABSTRACT
Irritable bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) are serious chronic diseases affecting millions of patients worldwide. Studies of human chemokine biology has suggested C-C chemokine receptor 9 (CCR9) may be a key mediator of pro-inflammatory signaling. Discovery of agents that inhibit CCR9 may lead to new therapies for CD and UC patients. Herein we describe the evolution of a high content screening hit (1) into potent inhibitors of CCR9, such as azaindole 12.
Subject(s)
Colitis, Ulcerative/drug therapy , Crohn Disease/drug therapy , Drug Discovery , Indoles/pharmacology , Receptors, CCR/antagonists & inhibitors , Colitis, Ulcerative/metabolism , Crohn Disease/metabolism , Dose-Response Relationship, Drug , Humans , Indoles/chemical synthesis , Indoles/chemistry , Molecular Structure , Receptors, CCR/metabolism , Structure-Activity RelationshipABSTRACT
Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, affects millions of people worldwide. CCR9 has been shown to be a key chemokine receptor mediating the local inflammatory responses in the GI tract. The CCR9 inhibitor Vercirnon advanced to phase 3 clinical trials, but carries several liabilities which we sought to improve.
Subject(s)
Inflammatory Bowel Diseases/drug therapy , Receptors, CCR/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Chemistry Techniques, Synthetic , Drug Evaluation, Preclinical/methods , Humans , Inhibitory Concentration 50 , Mice , Structure-Activity RelationshipABSTRACT
A mild and efficient library synthesis technique has been developed for the synthesis of ureas and carbamates from carbamic acids derived from the DBU-catalyzed reaction of amines and gaseous carbon dioxide. Carbamic acids derived from primary amines reacted with Mitsunobu reagents to generate isocyanates in situ which were condensed with primary and secondary amines to afford the desired ureas. Similarly, carbamic acids from secondary amines reacted with alcohols activated with Mitsunobu reagents to form carbamates.
