ABSTRACT
Gamma-secretase modulators (GSMs) selectively lower amyloid-ß42 (Aß42) and are therefore potential disease-modifying drugs for Alzheimer's disease (AD). Here, we report the discovery of imidazopyridine derivatives as GSMs with oral activity on not only Aß42 levels but also cognitive function. Structural optimization of the biphenyl group and pyridine-2-amide moiety of compound 1a greatly improved GSM activity and rat microsomal stability, respectively. 5-{8-[(3,4'-Difluoro[1,1'-biphenyl]-4-yl)methoxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-N-methylpyridine-2-carboxamide (1o) showed high in vitro potency and brain exposure, induced a robust reduction in brain Aß42 levels, and exhibited undetectable inhibition of cytochrome p450 enzymes. Moreover, compound 1o showed excellent efficacy against cognitive deficits in AD model mice. These findings suggest that compound 1o is a promising candidate for AD therapeutics.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Cognitive Dysfunction/drug therapy , Disease Models, Animal , Imidazoles/pharmacology , Pyridines/pharmacology , Administration, Oral , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Animals , Cell Line, Tumor , Cognitive Dysfunction/metabolism , Dose-Response Relationship, Drug , Humans , Imidazoles/administration & dosage , Imidazoles/chemistry , Male , Mice , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Pyridines/administration & dosage , Pyridines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Gamma-secretase modulators (GSMs) are promising disease-modifying drugs for Alzheimer's disease because they can selectively decrease pathogenic amyloid-ß42 (Aß42) levels. Here we report the discovery of orally active N-ethylpyridine-2-carboxamide derivatives as GSMs. The isoindolinone moiety of 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethyl-2,3-dihydro-1H-isoindol-1-one hydrogen chloride (1a) was replaced with a picolinamide moiety. Optimization of the benzyl group significantly improved GSM activity and mouse microsomal stability. 5-{8-[([1,1'-Biphenyl]-4-yl)methoxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-N-ethylpyridine-2-carboxamide hydrogen chloride (1v) potently reduced Aß42 levels with an IC50 value of 0.091⯵M in cultured cells without inhibiting CYP3A4. Moreover, 1v demonstrated a sustained pharmacokinetic profile and significantly reduced brain Aß42 levels in mice.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/metabolism , Drug Discovery , Enzyme Inhibitors/pharmacology , Pyridines/pharmacology , Administration, Oral , Alzheimer Disease/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Cell Line, Tumor , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Male , Mice , Mice, Inbred Strains , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Pyridines/administration & dosage , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazobenzimidazole scaffold. Compound 5a showed moderate inhibitory activity and good permeability, but unfavorable high P-glycoprotein (P-gp) liability for brain penetration. We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity. As a result, 6d was identified with improved P-gp liability and high PDE10A inhibitory activity. Compound 6d also showed satisfactory brain penetration, suppressed phencyclidine-induced hyperlocomotion and improved MK-801-induced working memory deficit.
Subject(s)
Phosphodiesterase Inhibitors/therapeutic use , Drug Design , Humans , Molecular Structure , Phosphodiesterase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Gamma-secretase modulators (GSMs) selectively inhibit the production of amyloid-ß 42 (Aß42) and may therefore be useful in the management of Alzheimer's disease. Most heterocyclic GSMs that are not derived from nonsteroidal anti-inflammatory drugs contain an arylimidazole moiety that potentially inhibits cytochrome P450 (CYP) activity. Here, we discovered imidazopyridine derivatives that represent a new class of scaffold for GSMs, which do not have a strongly basic end group such as arylimidazole. High-throughput screening identified 2-methyl-8-[(2-methylbenzyl)oxy]-3-(pyridin-4-yl)imidazo[1,2-a]pyridine (3a), which inhibited the cellular production of Aß42 (IC50â¯=â¯7.1⯵M) without changing total production of Aß. Structural optimization of this series of compounds identified 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethylisoindolin-1-one (3m) as a potent inhibitor of Aß42 (IC50â¯=â¯0.39⯵M) but not CYP3A4. Further, 3m demonstrated a sustained pharmacokinetic profile in mice and sufficiently penetrated the brain.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Drug Discovery , Heterocyclic Compounds/pharmacology , Imidazoles/pharmacology , Pyridines/pharmacology , Administration, Oral , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/biosynthesis , Animals , Cell Line, Tumor , Cytochrome P-450 CYP3A/metabolism , Dose-Response Relationship, Drug , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/chemistry , Humans , Imidazoles/administration & dosage , Imidazoles/chemistry , Injections, Intraperitoneal , Male , Mice , Mice, Inbred Strains , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/biosynthesis , Pyridines/administration & dosage , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
N-type calcium channels represent a promising target for the treatment of neuropathic pain. The selective N-type calcium channel blocker ziconotide ameliorates severe chronic pain but has a narrow therapeutic window and requires intrathecal administration. We identified tetrahydroisoquinoline derivative 1a as a novel potent N-type calcium channel blocker. However, this compound also exhibited potent inhibitory activity against hERG channels. Structural optimizations led to identification of (1S)-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-{[(1-hydroxycyclohexyl)methyl]amino}ethanone ((S)-1h), which exhibited high selectivity for hERG channels while retaining potency for N-type calcium channel inhibition. (S)-1h went on to demonstrate in vivo efficacy as an orally available N-type calcium channel blocker in a rat spinal nerve ligation model of neuropathic pain.
Subject(s)
Calcium Channel Blockers/chemistry , Calcium Channels, N-Type/metabolism , Ether-A-Go-Go Potassium Channels/metabolism , Tetrahydroisoquinolines/chemistry , Animals , Calcium Channel Blockers/metabolism , Calcium Channel Blockers/therapeutic use , Calcium Channels, N-Type/chemistry , Cell Line, Tumor , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/metabolism , Drug Evaluation, Preclinical , Ether-A-Go-Go Potassium Channels/chemistry , Humans , Male , Neuralgia/drug therapy , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tetrahydroisoquinolines/metabolism , Tetrahydroisoquinolines/therapeutic useABSTRACT
[structure: see text] A highly convergent synthetic route to the FGHIJKLM ring fragment of ciguatoxins has been developed, which relied on extensive use of the B-alkyl Suzuki-Miyaura coupling reaction.
