ABSTRACT
PI3Kδ plays a critical role in adaptive immune cell activation and function. Suppression of PI3Kδ has been shown to counter excessive triggering of immune responses which has led to delineating the role of this isoform in the pathophysiology of autoimmune disorders. In the current study, we have described preclinical characterization of PI3Kδ specific inhibitor LL-00071210 in various rheumatoid arthritis models. LL-00071210 displayed excellent in vitro potency in biochemical and cellular assay against PI3Kδ with IC50 values of 24.6 nM and 9.4 nM, respectively. LL-00071210 showed higher selectivity over PI3Kγ and PI3Kß as compared to available PI3K inhibitors. LL-00071210 had good stability in liver microsomes and plasma across species and showed low clearance, low-to-moderate Vss, with bioavailability of >50% in preclinical species. LL-00071210 demonstrated excellent in vivo efficacy in adjuvant-induced and collagen-induced arthritis models. Co-administration of LL-00071210 and methotrexate at subtherapeutic dose regimen in collagen induced arthritis model led to additive effects, indicating the combination potential of LL-00071210 along with available disease modifying anti-rheumatic drugs (DMARD). In conclusion, we have described a specific PI3Kδ inhibitor with â¼100-fold selectivity over other PI3K isoforms. LL-00071210 has good drug-like properties and thus warrants testing in the clinic for the treatment of autoimmune diseases.
Subject(s)
Arthritis, Rheumatoid , Phosphatidylinositol 3-Kinases , Arthritis, Rheumatoid/drug therapy , Humans , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Structure-Activity RelationshipABSTRACT
α7 nicotinic acetylcholine receptor (α7 nAChR) is an extensively validated target for several neurological and psychiatric conditions namely, dementia and schizophrenia, owing to its vital roles in cognition and sensorimotor gating. Positive allosteric modulation (PAM) of α7 nAChR represents an innovative approach to amplify endogenous cholinergic signaling in a temporally restricted manner in learning and memory centers of brain. α7 nAChR PAMs are anticipated to side-step burgeoning issues observed with several clinical-stage orthosteric α7 nAChR agonists, related to selectivity, tolerance/tachyphylaxis, thus providing a novel dimension in therapeutic strategy and pharmacology of α7 nAChR ion-channel. Here we describe a novel α7 nAChR PAM, LL-00066471, which potently amplified agonist-induced Ca2+ fluxes in neuronal IMR-32 neuroblastoma cells in a α-bungarotoxin (α-BTX) sensitive manner. LL-00066471 showed excellent oral bioavailability across species (mouse, rat and dog), low clearance and good brain penetration (B/P ratio > 1). In vivo, LL-00066471 robustly attenuated cognitive deficits in both procognitive and antiamnesic paradigms of short-term episodic and recognition memory in novel object recognition task (NORT) and social recognition task (SRT), respectively. Additionally, LL-00066471 mitigated apomorphine-induced sensorimotor gating deficits in acoustic startle reflex (ASR) and enhanced antipsychotic efficacy of olanzapine in conditioned avoidance response (CAR) task. Further, LL-00066471 corrected redox-imbalances and reduced cortico-striatal infarcts in stroke model. These finding together suggest that LL-00066471 has potential to symptomatically alleviate cognitive deficits associated with dementias, attenuate sensorimotor gating deficits in schizophrenia and correct redox-imbalances in cerebrovascular disorders. Therefore, LL-00066471 presents potential for management of cognitive impairments associated with neurological and psychiatric conditions.
Subject(s)
Behavior, Animal/drug effects , Brain/drug effects , Cholinergic Agents/pharmacology , Cognition/drug effects , Cognitive Dysfunction/prevention & control , Gait Disorders, Neurologic/prevention & control , Sensory Gating/drug effects , alpha7 Nicotinic Acetylcholine Receptor/drug effects , Animals , Brain/metabolism , Brain/physiopathology , Cell Line, Tumor , Cholinergic Agents/pharmacokinetics , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/physiopathology , Cognitive Dysfunction/psychology , Disease Models, Animal , Dogs , Exploratory Behavior/drug effects , Gait Disorders, Neurologic/metabolism , Gait Disorders, Neurologic/physiopathology , Gait Disorders, Neurologic/psychology , Ischemic Stroke/drug therapy , Ischemic Stroke/metabolism , Ischemic Stroke/physiopathology , Male , Mice, Inbred BALB C , Open Field Test/drug effects , Oxidative Stress/drug effects , Rats, Sprague-Dawley , Rats, Wistar , Reflex, Startle/drug effects , Signal Transduction , Social Behavior , alpha7 Nicotinic Acetylcholine Receptor/metabolismABSTRACT
A new class of potent dopamine D(4) antagonists was discovered with selectivity over dopamine D(2) and the alpha-1 adrenoceptor. The lead compound was discovered by screening our compound collection. The structure-activity relationships of substituted isoindoline rings and the chirality about the hydroxymethyl side chain were explored. The isoindoline analogues showed modest differences in potency and selectivity. The S enantiomer proved to be the more potent enantiomer at the D(4) receptor. Several analogues with greater than 100-fold selectivity for D(4) over D(2) and the alpha-1 adrenoreceptor were discovered. Several selective analogues were active in vivo upon oral or intraperitoneal administration. A chiral synthesis starting from either D- or L-O-benzylserine is also described.
Subject(s)
Dopamine D2 Receptor Antagonists , Indoles/chemistry , Indoles/pharmacology , Isoxazoles/chemistry , Isoxazoles/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Administration, Oral , Animals , Apomorphine/pharmacology , Benzyl Compounds/chemical synthesis , Benzyl Compounds/chemistry , Benzyl Compounds/pharmacology , Dizocilpine Maleate/metabolism , Indoles/chemical synthesis , Indoles/metabolism , Infusions, Parenteral , Isoxazoles/chemical synthesis , Piperidines/chemical synthesis , Prazosin/metabolism , Prazosin/pharmacology , Rats , Receptors, Dopamine D4 , Serine/analogs & derivatives , Serine/chemistry , Spiperone/metabolism , Spiperone/pharmacology , Stereoisomerism , Structure-Activity Relationship , Substrate SpecificityABSTRACT
2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) potentiators are ligands that act as positive allosteric modulators at the AMPA receptors. We recently disclosed a novel series of 2-arylpropylsulfonamides that were potent potentiators of responses mediated through AMPA receptors. To further define the structural requirements for activity in this series, new ring-constrained analogues were prepared and a new stereocenter was introduced. The potentiating activity was highly dependent on the stereochemistry at the 2-position of the disubstituted cyclopentane and was independent of the relative stereochemistry at the 1-position. Compound (R,R)-10 represents a potent, novel potentiator of iGluR4 flip receptors (EC(50) = 22.6 nM).