ABSTRACT
A multi-technique approach was applied in order to fully characterize four low-level unknown impurities of GW876008, a novel CRF(1) receptor antagonist. Liquid chromatography (LC)-NMR spectroscopy was used in combination with LC-MS to obtain detailed information regarding the structure of the two major impurities present in batches of GW876008 and observed in the first synthetic scale-up for preclinical use. Two additional impurities were unexpectedly found at greater levels in a large scale synthesis for clinical use and their structure was elucidated by means of high resolution (HR)-MS and HR-NMR, after a small scale preparative HPLC purification step. This structural information was useful in terms of shedding light on the typical impurity profile of this new chemical entity with the aim to support the early development package for Phase I clinical studies.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/analysis , Chromatography, High Pressure Liquid/methods , Drug Contamination , Magnetic Resonance Spectroscopy/methods , Pyrazoles/analysis , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Spectrometry, Mass, Electrospray Ionization/methods , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Pyrazoles/chemistryABSTRACT
A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.
Subject(s)
Indenes/chemical synthesis , Pyridines/chemical synthesis , Receptors, AMPA/physiology , Sulfonamides/chemical synthesis , Administration, Oral , Allosteric Regulation , Animals , Biological Availability , Blood Proteins/metabolism , Blood-Brain Barrier/metabolism , Callithrix , Cell Line , Crystallography, X-Ray , Dogs , Humans , Indenes/pharmacokinetics , Indenes/pharmacology , Macaca fascicularis , Male , Microsomes, Liver/metabolism , Models, Molecular , Protein Binding , Protein Structure, Tertiary , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Species Specificity , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacologyABSTRACT
To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.
Subject(s)
Pyridines/chemical synthesis , Pyridines/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , Exploratory Behavior/drug effects , Female , Forelimb/drug effects , Gerbillinae , Humans , Male , Models, Chemical , Molecular Structure , Motor Activity/drug effects , Psychological Tests , Pyridines/chemistry , Pyrroles/chemistry , Rats , Rats, Sprague-Dawley , Stereoisomerism , Ultrasonics , Vocalization, Animal/drug effectsABSTRACT
Exploiting the SAR of the known pyrrole derivatives, a new class of mGluR1 antagonists was designed by replacement of the pyrrole core with an indole scaffold and consequent cyclization of the C-2 position into a tricyclic beta-carboline template. The appropriate exploration of the position C-6 with a combination of H-bond acceptor groups coupled with bulky/lipophilic moieties led to the discovery of a new series of mGluR1 antagonists. These compounds exhibited a non-competitive behavior, excellent pharmacokinetic properties, and good in vivo activity in animal models of acute and chronic pain, after oral administration.
