ABSTRACT
There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound LDN-214117. Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.
Subject(s)
Activin Receptors, Type I/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Diffuse Intrinsic Pontine Glioma/drug therapy , Protein Kinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Drug Discovery , Female , HEK293 Cells , Humans , Male , Mice, SCID , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The identification and hit-to-lead exploration of a novel, potent and selective series of histamine H(4) receptor inverse agonists is described. The initial hit, 3A (IC(50) 19 nM) was identified by means of a ligand-based virtual screening approach. Subsequent medicinal chemistry exploration yielded 18I which possessed increased potency (R-enantiomer IC(50) 1 nM) as well as enhanced microsomal stability.
Subject(s)
Histamine Antagonists/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Animals , Biological Availability , Drug Discovery , Histamine Antagonists/chemistry , Histamine Antagonists/pharmacokinetics , Inhibitory Concentration 50 , Macaca fascicularis , Rats , Receptors, Histamine , Receptors, Histamine H4 , StereoisomerismABSTRACT
We have modified the previously reported 2-aminoquinoline 1 to provide two novel series of MCH-1R antagonists. Representative compounds from the quinazoline and benzimidazole series have been shown to be potent and selective, with promising in vitro eADME profiles.
Subject(s)
Benzimidazoles/chemical synthesis , Quinazolines/chemical synthesis , Receptors, Somatostatin/antagonists & inhibitors , Benzimidazoles/pharmacology , Humans , Inhibitory Concentration 50 , Protein Binding , Quinazolines/pharmacology , Structure-Activity RelationshipABSTRACT
A new series of 2-aminoquinolines has been identified as antagonists of the melanin concentrating hormone receptor (MCH-1R). Syntheses and structure-activity relationships are described leading to a compound having low nanomolar activity against the receptor and demonstrating functional antagonism. Studies also showed that some of the compounds were selective against a range of other G protein-coupled receptors.
