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1.
Org Biomol Chem ; 17(35): 8166-8174, 2019 09 21.
Article in English | MEDLINE | ID: mdl-31464336

ABSTRACT

Continuous flow-flash synthesis of a 2-bromobenzaldehyde derivative 18 as a key intermediate of a novel cholinergic muscarinic M1 positive allosteric modulator 1 bearing an isoindolin-1-one ring system as a pharmacophore has been achieved using flow microreactors through selective I/Li exchange of 1-bromo-2-iodobenzene derivative 17 with BuLi and subsequent formylation at -40 °C of the highly reactive 2-bromophenyllithium intermediate using DMF, which is difficult to achieve by a conventional batch process due to the conversion of the highly reactive 2-bromophenyllithium intermediate into benzyne even at -78 °C. Late-stage cyclization to give the isoindolin-1-one ring system, through reductive amination of 18 followed by palladium-catalyzed carbonylation with carbon monoxide and intramolecular cyclization, efficiently afforded 1 for its further research and development.


Subject(s)
Benzaldehydes/pharmacology , Cholinergic Agents/pharmacology , Receptor, Muscarinic M1/metabolism , Allosteric Regulation/drug effects , Benzaldehydes/chemical synthesis , Benzaldehydes/chemistry , Cholinergic Agents/chemical synthesis , Cholinergic Agents/chemistry , Humans , Molecular Structure
2.
J Med Chem ; 61(7): 2973-2988, 2018 04 12.
Article in English | MEDLINE | ID: mdl-29510038

ABSTRACT

A series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower log  D value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [ cis-3-({(5 R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound 10 exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound 10 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.


Subject(s)
Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Receptors, Retinoic Acid/agonists , Animals , Autoimmune Diseases/drug therapy , Drug Discovery , Drug Inverse Agonism , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Gene Expression/drug effects , Genes, Reporter/drug effects , Interleukin-17/genetics , Interleukin-17/metabolism , Interleukin-23 Subunit p19/genetics , Interleukin-23 Subunit p19/metabolism , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Th17 Cells/immunology
3.
Bioorg Med Chem ; 26(2): 483-500, 2018 01 15.
Article in English | MEDLINE | ID: mdl-29262987

ABSTRACT

A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration.


Subject(s)
Drug Discovery , Glycine/analogs & derivatives , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Administration, Oral , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Glycine/administration & dosage , Glycine/chemistry , Glycine/pharmacology , Humans , Jurkat Cells , Male , Mice , Mice, Inbred BALB C , Models, Animal , Models, Molecular , Molecular Structure , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Structure-Activity Relationship
4.
J Med Chem ; 60(21): 8963-8981, 2017 11 09.
Article in English | MEDLINE | ID: mdl-29023121

ABSTRACT

The discovery and optimization of Δ-5 desaturase (D5D) inhibitors are described. Investigation of the 1,3-oxazolidin-2-one scaffold was inspired by a pharmacophore model constructed from the common features of several hit compounds, resulting in the identification of 3,5-diphenyl-1,3-oxazolidin-2-one 5h as a novel lead showing potent in vitro activity. Subsequent optimization focused on the modification of two metabolic sites, which provided (4S,5S)-5i, a derivative with improved metabolic stability. Moreover, adding a substituent into the upper phenyl moiety further enhanced the intrinsic activity, which led to the discovery of 5-[(4S,5S)-5-(4fluorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]benzene-1,3-dicarbonitrile (4S,5S)-5n, endowed with excellent D5D binding affinity, cellular activity, and high oral bioavailability in a mouse. It exhibited robust in vivo hepatic arachidonic acid/dihomo-γ-linolenic acid ratio reduction (a target engagement marker) in an atherosclerosis mouse model. Finally, an asymmetric synthetic procedure for this compound was established.


Subject(s)
Fatty Acid Desaturases/antagonists & inhibitors , Oxazolidinones/pharmacology , Administration, Oral , Animals , Arachidonic Acid/metabolism , Atherosclerosis/drug therapy , Biological Availability , Delta-5 Fatty Acid Desaturase , Drug Discovery/methods , Liver/metabolism , Mice , Oxazolidinones/chemical synthesis , Oxazolidinones/metabolism , Oxazolidinones/pharmacokinetics , Structure-Activity Relationship
5.
J Med Chem ; 55(9): 4336-51, 2012 May 10.
Article in English | MEDLINE | ID: mdl-22490048

ABSTRACT

Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K(+) channel inhibition in a patch-clamp study. To decrease hERG K(+) channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K(+) channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3-[(1R)-1-{[2-(acetylamino)ethyl]amino}ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule's absolute configuration.


Subject(s)
Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Benzamides/pharmacology , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Obesity/drug therapy , Quinolines/pharmacology , Receptors, Pituitary Hormone/antagonists & inhibitors , Animals , Anti-Obesity Agents/chemical synthesis , Benzamides/chemical synthesis , Benzamides/chemistry , CHO Cells , Cricetinae , Ether-A-Go-Go Potassium Channels/genetics , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Inhibitory Concentration 50 , Ligands , Magnetic Resonance Spectroscopy , Molecular Dynamics Simulation , Obesity/genetics , Obesity/metabolism , Quinolines/chemical synthesis , Quinolines/chemistry , Rats , Rats, Inbred F344 , Receptors, Pituitary Hormone/metabolism , Spectrometry, Mass, Electrospray Ionization , Stereoisomerism , Structure-Activity Relationship
6.
J Med Chem ; 55(5): 2353-66, 2012 Mar 08.
Article in English | MEDLINE | ID: mdl-22309223

ABSTRACT

It was found that 3-(aminomethyl)quinoline derivatives showed high binding affinities for melanin-concentrating hormone receptor 1 (MCHR1) with reduced affinity for serotonin receptor 2c (5-HT2c) when the dihydronaphthalene nucleus of compound 1 (human MCHR1, IC(50) = 1.9 nM; human 5-HT2c receptor, IC(50) = 0.53 nM) was replaced by other bicyclic core scaffolds. Among the synthesized compounds, 8-methylquinoline derivative 5v especially showed high binding affinity (IC(50) = 0.54 nM), potent in vitro antagonistic activity (IC(50) = 2.8 nM) for MCHR1, and negligible affinity for 5-HT2c receptor (IC(50) > 1000 nM). Oral administration of 5v significantly and dose-dependently suppressed nocturnal food intake in diet-induced obese rats and did not affect food intake in MCHR1-deficient mice. These results and rat pharmacokinetic study findings suggested that compound 5v is a highly potent, orally bioavailable, and centrally acting nonpeptide MCHR1 antagonist.


Subject(s)
Anti-Obesity Agents/chemical synthesis , Benzamides/chemical synthesis , Quinolines/chemical synthesis , Receptors, Somatostatin/antagonists & inhibitors , Administration, Oral , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Benzamides/pharmacokinetics , Benzamides/pharmacology , Biological Availability , Eating/drug effects , Humans , Mice , Mice, Knockout , Quinolines/pharmacokinetics , Quinolines/pharmacology , Rats , Receptor, Serotonin, 5-HT2C/metabolism , Receptors, Somatostatin/genetics , Structure-Activity Relationship
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