ABSTRACT
We report the identification and synthesis of a series of aminopyrimidin-4-one IRAK4 inhibitors. Through high throughput screening, an aminopyrimidine hit was identified and modified via structure enabled design to generate a new, potent, and kinase selective pyrimidin-4-one chemotype. This chemotype is exemplified by compound 16, which has potent IRAK4 inhibition activity (IC50 = 27 nM) and excellent kinase selectivity (>100-fold against 99% of 111 tested kinases), and compound 31, which displays potent IRAK4 activity (IC50 = 93 nM) and good rat bioavailability (F = 42%).
ABSTRACT
IRAK4 plays a key role in TLR/IL-1 signaling. Previous efforts identified a series of aminopyrimidine IRAK4 inhibitors that possess good potency, but modest kinase selectivity. Exploration of substituents at the C-2 and C-5 positions generated compounds that maintained IRAK4 potency and improved kinase selectivity. Additionally, it was found that the pyrimidine core could be replaced with a pyridine and still retain potency and kinase selectivity. The optimization efforts led to compound 26 which had an IRAK4 IC50 of 0.7 nM, an IC50 of 55 nM on THP-1 cells stimulated with LPS, a TLR4 agonist, and greater than 100-fold selectivity versus 96% of a panel of 306 kinases.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cell Line , High-Throughput Screening Assays , Humans , Lipopolysaccharides/pharmacology , Structure-Activity Relationship , Substrate Specificity , Toll-Like Receptor 4/antagonists & inhibitorsABSTRACT
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Na(v)1.7 inhibitory activity and moderate selectivity over Na(v)1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 µM.
Subject(s)
Analgesics/pharmacology , Ganglia, Spinal/drug effects , NAV1.7 Voltage-Gated Sodium Channel/chemistry , Neuralgia/drug therapy , Sodium Channel Blockers/pharmacology , Spinal Nerves/drug effects , Spiro Compounds/pharmacology , Analgesics/chemistry , Animals , Molecular Structure , Patch-Clamp Techniques , Quinoxalines/chemistry , Rats , Sodium Channel Blockers/chemistry , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized and displayed potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. Compound 41 displayed anti-nociceptive efficacy in the rat CFA pain model at 100 mpk oral dosing.
Subject(s)
Drug Discovery , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Quinoxalines/pharmacology , Sodium Channel Blockers/pharmacology , Spiro Compounds/pharmacology , Dose-Response Relationship, Drug , Humans , Molecular Structure , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemistry , Pyrimidinones/chemistry , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Thiophenes/chemistry , Administration, Oral , Animals , Chronic Pain/drug therapy , Disease Models, Animal , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Pyrimidinones/chemical synthesis , Pyrimidinones/therapeutic use , Rats , Receptors, Metabotropic Glutamate/metabolism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/therapeutic useABSTRACT
Novel P2X(7) antagonists were developed using a purine scaffold. These compounds were potent and selective at the P2X(7) receptor in human and rodent as well as efficacious in rodent pain models. Compound 15a was identified to have oral potency in several pain models in rodent similar to naproxen, gabapentin and pregabalin. Structure-activity relationship (SAR) development and results of pain models are presented.
Subject(s)
Pain/drug therapy , Purinergic P2X Receptor Antagonists/chemical synthesis , Purines/chemical synthesis , Receptors, Purinergic P2X7/chemistry , Animals , Humans , Purinergic P2X Receptor Antagonists/chemistry , Purinergic P2X Receptor Antagonists/therapeutic use , Purines/chemistry , Purines/therapeutic use , Rats , Receptors, Purinergic P2X7/metabolism , Structure-Activity RelationshipABSTRACT
Structure-activity relationship (SAR) efforts around our initial lead compound 1 led to the identification of potent P2X(7) receptor antagonists with improved pharmacokinetic profiles. These compounds were potent and selective at the P2X(7) receptor in both human and rodent. Compound (entry 31) exhibited oral efficacy in the rat MIA and CCI pain models.
Subject(s)
Analgesics/chemical synthesis , Drug Design , Pain , Purinergic P2 Receptor Antagonists/chemical synthesis , Administration, Oral , Analgesics/chemistry , Animals , Disease Models, Animal , Humans , Molecular Structure , Pain/drug therapy , Purinergic P2 Receptor Antagonists/chemistry , Rats , Receptors, Purinergic P2X7/metabolism , Structure-Activity RelationshipABSTRACT
A series of 2,4-diphenyl-1H-imidazole analogs have been synthesized and displayed potent human CB2 agonist activity. Many of these analogs showed high functional selectivity over human CB1 receptors. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described.
Subject(s)
Imidazoles/chemistry , Pain/drug therapy , Receptor, Cannabinoid, CB2/agonists , Administration, Oral , Animals , Chronic Disease , Humans , Imidazoles/pharmacokinetics , Imidazoles/therapeutic use , Rats , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity RelationshipABSTRACT
A series of N-8 substituted analogs based upon the spiropiperidine core of the original lead compound 1 was synthesized. This lead has been elaborated to compounds to give compounds 2 and 3 (R=H) that exhibited high NOP binding affinity as well as selectivity against other known opioid receptors. These two series have been further functionalized at the amido nitrogen. The synthesis and structure-activity relationship (SAR) of these and related compounds are discussed.
Subject(s)
Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, Opioid/drug effects , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Animals , Binding Sites , Capsaicin/pharmacology , Combinatorial Chemistry Techniques , Cough/chemically induced , Disease Models, Animal , Drug Design , Guinea Pigs , Molecular Structure , Piperidines/chemistry , Receptors, Opioid/metabolism , Spiro Compounds/chemistry , Structure-Activity Relationship , Nociceptin ReceptorABSTRACT
Orphanin FQ/nociceptin (OFQ/N) is the endogenously occurring peptide ligand for the nociceptin opioid receptor (NOP) that produces anxiolytic-like effects in mice and rats. The present study assessed the anxiolytic-like activity of 8-[bis(2-methylphenyl)-methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510), a novel potent piperidine NOP agonist (EC(50) = 12 nM) that binds with high affinity (K(i) = 0.3 nM) and functional selectivity (>50-fold over the mu-, kappa-, and delta-opioid receptors). The anxiolytic-like activity and side-effect profile of SCH 221510 were assessed in a variety of models and the benzodiazepine, chlordiazepoxide (CDP), was included for comparison. The effects of chronic dosing of SCH 221510 were also assessed. Furthermore, the specificity of the anxiolytic-like effect of SCH 221510 was investigated with the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and the opioid receptor antagonist naltrexone. Like CDP (1-30 mg/kg i.p.), SCH 221510 (1-30 mg/kg p.o.) produced anxiolytic-like effects in the elevated plus-maze (rat and gerbil), Vogel conflict (rat), conditioned lick suppression (rat), fear-potentiated startle (rat), and pup separation-induced vocalization (guinea pig) assays. In the Vogel conflict, the anxiolytic-like effect of SCH 221510 (10 mg/kg) was attenuated by J-113397 (3-10 mg/kg p.o.), but not naltrexone (3-30 mg/kg i.p.). Additionally, the anxiolytic-like effects of SCH 221510 did not change appreciably following 14-day b.i.d. dosing in rats (10 mg/kg). Furthermore, unlike CDP, SCH 221510 (3-30 mg/kg) produced anxiolytic-like activity at doses that did not disrupt overt behavior. Collectively, these data suggest that NOP agonists such as SCH 221510 may have an anxiolytic-like profile similar to benzodiazepines, with a reduced side-effect liability.
Subject(s)
Anti-Anxiety Agents/pharmacology , Azabicyclo Compounds/pharmacology , Behavior, Animal/drug effects , Receptors, Opioid/agonists , Animals , Animals, Newborn , Anti-Anxiety Agents/chemistry , Azabicyclo Compounds/chemistry , Benzimidazoles/pharmacology , CHO Cells , Cricetinae , Cricetulus , Female , Gerbillinae , Guinea Pigs , Humans , Male , Molecular Structure , Narcotic Antagonists , Piperidines/pharmacology , Protein Binding , Rats , Rats, Wistar , Receptors, Opioid/metabolism , Nociceptin ReceptorABSTRACT
A series of N-substituted analogs based upon the spiropiperidine core of 1 was synthesized and exhibited high binding affinity to the nociceptin (NOP) receptor. The selectivities against other known opioid receptors were determined.
Subject(s)
Piperidines/chemical synthesis , Receptors, Opioid/agonists , Administration, Oral , Animals , Cough/drug therapy , Drug Evaluation, Preclinical , Guanosine 5'-O-(3-Thiotriphosphate) , Ligands , Pharmacokinetics , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protein Binding , Rats , Receptors, Opioid/metabolism , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity Relationship , Nociceptin ReceptorABSTRACT
A novel series of 3-substituted-8-aryl-[1,2,4]-triazolo[5,1-i]purin-5-amine analogs related to Sch 58261 was synthesized in order to identify potent adenosine A(2A) receptor antagonists with improved selectivity over the A(1) receptor, physiochemical properties, and pharmacokinetic profiles as compared to those of Sch 58261. As a result of structural modifications, numerous analogs with excellent in vitro binding affinities and selectivities were identified. Moreover, compound 27 displayed both superior in vitro and highly promising in vivo profiles.
Subject(s)
Adenosine A2 Receptor Antagonists , Neuroprotective Agents/pharmacology , Purines/chemical synthesis , Purines/pharmacology , Pyrimidines/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacology , Adenosine A1 Receptor Antagonists , Chemical Phenomena , Chemistry, Physical , Indicators and Reagents , Magnetic Resonance Spectroscopy , Structure-Activity RelationshipABSTRACT
The structure-activity relationship (SAR) exploration using 2-(2-furanyl)-7-phenyl[1,2,4]triazolo-[1,5-c]pyrimidin-5-amine (1) as a template led to the identification of a novel class of potent and selective adenosine A2A receptor (AR) antagonists. However, these compounds were found to be associated with significant hERG activity. This report discusses the strategy and outcome of an expanded SAR focused on addressing the hERG liability. As a result, compounds 21 and 24 possess excellent in vitro profiles, highly promising in vivo profiles, and acceptable levels of hERG channel inhibition.
Subject(s)
Adenosine A2 Receptor Antagonists , Pyrimidines/pharmacology , Triazoles/pharmacology , Administration, Oral , Animals , Catalepsy/drug therapy , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Molecular Structure , Motor Activity/drug effects , Pyrimidines/chemistry , Pyrimidines/classification , Pyrimidines/therapeutic use , Rats , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/therapeutic useABSTRACT
The structure-activity relationship of this novel class of compounds based on 2-(2-furanyl)-7-phenyl[1,2,4]-triazolo[1,5-c]pyrimidin-5-amine, 1, and its analogs was evaluated for their in vitro and in vivo adenosine A(2A) receptor antagonism. Several compounds displayed oral activity at 3 mg/kg in a rat catalepsy model. Specifically, compound 8g displayed an excellent in vitro profile, as well as a highly promising in vivo profile.
Subject(s)
Adenosine A2 Receptor Antagonists , Pyrimidines/pharmacology , Triazoles/pharmacology , Administration, Oral , Animals , Catalepsy/drug therapy , Disease Models, Animal , Drug Evaluation, Preclinical , Male , Molecular Structure , Pyrimidines/chemistry , Pyrimidines/classification , Pyrimidines/therapeutic use , Rats , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/therapeutic useABSTRACT
In high throughput screening of our file compounds, a novel structure 1 was identified as a potent A(2A) receptor antagonist with no selectivity over the A1 adenosine receptor. The structure-activity relationship investigation using 1 as a template lead to identification of a novel class of compounds as potent and selective antagonists of A(2A) adenosine receptor. Compound 26 was identified to be the most potent A(2A) receptor antagonist (Ki = 0.8 nM) with 100-fold selectivity over the A1 adenosine receptor.