ABSTRACT
The identification of clinical candidate LY3522348 (compound 23) is described. LY3522348 is a highly selective, oral dual inhibitor of human ketohexokinase isoforms C and A (hKHK-C, hKHK-A). Optimization began with highly efficient (S)-2-(2-methylazetidin-1-yl)-6-(1H-pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile (3). Efforts focused on developing absorption, distribution, metabolism, potency, and in vitro safety profiles to support oral QD dosing in patients. Structure-based design leveraged vectors for substitution of the pyrazole ring, which provided an opportunity to interact with several different proximal amino acid residues in the protein. LY3522348 displayed a robust pharmacodynamic response in a mouse model of fructose metabolism and was advanced into clinical trials.
Subject(s)
Fructokinases , Mice , Animals , HumansABSTRACT
The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.
Subject(s)
Isoquinolines/pharmacology , Pain/drug therapy , Prodrugs/pharmacology , Receptors, Kainic Acid/antagonists & inhibitors , Administration, Oral , Amino Acid Sequence , Animals , Disease Models, Animal , Haplorhini , Isoquinolines/chemistry , Molecular Sequence Data , Prodrugs/chemistry , Receptors, Kainic Acid/chemistry , Structure-Activity RelationshipABSTRACT
We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.
Subject(s)
Isoquinolines/pharmacology , Pain/drug therapy , Prodrugs/pharmacology , Receptors, Kainic Acid/antagonists & inhibitors , Tetrazoles/pharmacology , Administration, Oral , Amino Acid Sequence , Animals , Disease Models, Animal , Isoquinolines/chemistry , Male , Molecular Sequence Data , Prodrugs/chemistry , Rats , Rats, Sprague-Dawley , Receptors, Kainic Acid/chemistry , Structure-Activity Relationship , Tetrazoles/chemistryABSTRACT
Amino acids 5 and 7, two potent and selective competitive GluR5 KA receptor antagonists, exhibited high GluR5 receptor affinity over other glutamate receptors. Their ester prodrugs 6 and 8 were orally active in three models of pain: reversal of formalin-induced paw licking, carrageenan-induced thermal hyperalgesia, and capsaicin-induced mechanical hyperalgesia.
Subject(s)
Amino Acids/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Pain/drug therapy , Receptors, Kainic Acid/antagonists & inhibitors , Analgesics/pharmacokinetics , Animals , Biological Availability , Cell Line , Disease Models, Animal , Humans , Hyperalgesia/drug therapy , Rats , Receptors, AMPA/metabolism , Recombinant Proteins/metabolism , Spinal Cord/physiopathology , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolismABSTRACT
Amino diacid 3, a highly selective competitive GluR5 kainate receptor antagonist, exhibited high GluR5 receptor affinity and selectivity over other glutamate receptors. Its diethyl ester prodrug 4 was orally active in two models of migraine: the neurogenic dural plasma protein extravasation model and the nucleus caudalis c-fos expression model. These data suggest that a GluR5 kainate receptor antagonist might be an efficacious antimigraine therapy with a novel mechanism of action.
