ABSTRACT
This paper describes the structure-activity-relationships of novel fluoroalkyl substituents at the C2 position of iminothiazine dioxide beta secretase inhibitors. Key discoveries include reduced amidine basicity and its effect on Pgp, cell potency, and efficacy in various preclinical in vivo efficacy animal models. Findings from these structure-activity-relationships are discussed.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Oxides/pharmacology , Thiazines/pharmacology , Administration, Oral , Amyloid Precursor Protein Secretases/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , HEK293 Cells , Humans , Molecular Structure , Oxides/administration & dosage , Oxides/chemistry , Rats , Structure-Activity Relationship , Thiazines/administration & dosage , Thiazines/chemistryABSTRACT
Iridium catalysts containing dative nitrogen ligands are highly active for the borylation and silylation of C-H bonds, but chiral analogs of these catalysts for enantioselective silylation reactions have not been developed. We report a new chiral pyridinyloxazoline ligand for enantioselective, intramolecular silylation of symmetrical diarylmethoxy diethylsilanes. Regioselective and enantioselective silylation of unsymmetrical substrates was also achieved in the presence of this newly developed system. Preliminary mechanistic studies imply that C-H bond cleavage is irreversible, but not the rate-determining step.
Subject(s)
Iridium/chemistry , Nitrogen/chemistry , Oxazoles/chemistry , Silanes/chemical synthesis , Catalysis , Ligands , Molecular Structure , Silanes/chemistry , StereoisomerismABSTRACT
In this paper we describe our strategy to improve the aqueous solubility of SCH 900229, a potent PS1-selective γ-secretase inhibitor for the treatment of Alzheimer's disease. Incorporation of ionizable amino groups into the side chain terminal generates water soluble ß-aminosulfone analogues of SCH 900229 that maintain robust in vitro potency and in vivo efficacy.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Benzopyrans/chemistry , Benzopyrans/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Sulfones/chemistry , Sulfones/pharmacology , Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases/metabolism , Animals , Benzopyrans/pharmacokinetics , Dogs , Drug Design , Enzyme Inhibitors/pharmacokinetics , Haplorhini , Humans , Rats , Solubility , Sulfones/pharmacokinetics , Water/chemistryABSTRACT
Molecular modeling of unbound tricyclic guanine scaffolds indicated that they can serve as effective bioisosteric replacements of xanthines. This notion was further confirmed by a combination of X-ray crystallography and SAR studies, indicating that tricyclic guanine DPP4 inhibitors mimic the binding mode of xanthine inhibitors, exemplified by linagliptin. Realization of the bioisosteric relationship between these scaffolds potentially will lead to a wider application of cyclic guanines as xanthine replacements in drug discovery programs for a variety of biological targets. Newly designed DPP4 inhibitors achieved sub-nanomolar potency range and demonstrated oral activity in vivo in mouse glucose tolerance test.
Subject(s)
Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Guanine/pharmacology , Xanthines/pharmacology , Animals , Blood Glucose/drug effects , Crystallography, X-Ray , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dose-Response Relationship, Drug , Glucose Tolerance Test , Guanine/analogs & derivatives , Guanine/chemistry , Humans , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Xanthines/administration & dosage , Xanthines/chemistryABSTRACT
In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery, we have elaborated this scaffold into a very potent and selective DPP-4 inhibitor lead series, as highlighted by compound 17c.
ABSTRACT
In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer's disease (AD), demonstrating reduction of amyloid-ß (Aß) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a(-) features improved selectivity for the inhibition of the PS-1 isoform of γ-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Drug Discovery/methods , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Biological Availability , Central Nervous System/drug effects , Central Nervous System/metabolism , Cytochrome P-450 CYP2C9/metabolism , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/pharmacokinetics , HEK293 Cells , Humans , Molecular Conformation , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/pharmacologyABSTRACT
An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Sulfones/chemical synthesis , Sulfones/pharmacology , Benzopyrans/chemistry , Cyclization , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Molecular Structure , Pyrans/chemical synthesis , Pyrans/chemistry , Pyrans/pharmacology , Structure-Activity Relationship , Sulfones/chemistryABSTRACT
Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor™ led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene γ-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a γ-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering Aß40-42, compared to their parent compounds.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Benzopyrans/chemistry , Enzyme Inhibitors/chemistry , Sulfones/chemistry , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Benzoquinones/chemical synthesis , Benzoquinones/chemistry , Benzoquinones/pharmacology , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Fluorine/chemistry , Fluorine/pharmacology , Humans , Molecular Structure , Oxidation-Reduction , Sulfones/chemical synthesis , Sulfones/pharmacologyABSTRACT
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
A series of fused tricyclic mGluR1 antagonists containing a pyridone ring were synthesized. In vitro, these antagonists were potent against both human and rat isozymes, as well as selective for inhibiting mGluR1 over mGluR5. When dosed orally, several examples were active in vivo in a rat SNL test.
Subject(s)
Pyridones/chemical synthesis , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Administration, Oral , Analgesics/pharmacology , Animals , Cells, Cultured , Cyclization , Humans , Inhibitory Concentration 50 , Molecular Structure , Neuralgia/drug therapy , Protein Binding/drug effects , Pyridones/chemistry , Pyridones/pharmacology , RatsABSTRACT
An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aß40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aß after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease.
ABSTRACT
Complex tetracyclic sulfones were designed as gamma-secretase inhibitors and a stereoselective synthesis was achieved. Gamma-secretase activity was seen predominately in the (-) enantiomeric series. Compounds such as 2a and 2b showed remarkable in vitro and in vivo potency.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Sulfones/chemistry , Amyloid beta-Peptides/antagonists & inhibitors , Animals , Drug Design , Hepatocytes/metabolism , Humans , Mice , Stereoisomerism , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/pharmacologyABSTRACT
A novel series of tricyclic gamma-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous gamma-secretase inhibitors.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Receptors, Notch/drug effects , Sulfones/chemistry , Sulfones/pharmacology , Animals , Crystallography, X-Ray , Drug Design , Mice , Models, Molecular , Sulfones/chemical synthesisABSTRACT
Metabotropic glutamate receptor 1 (mGluR1) plays important roles in the neurotransmission and pathogenesis of several neurological disorders, including chronic pain. Antagonists of mGlur1 are suggested to be useful for the treatment of pain. Herein, we report the discovery of a novel series of tetracyclic mGluR1 antagonists, such as 23c and 23e, with oral efficacy of ED50 of 8 and 5.1 mg/kg, respectively, in rat spinal nerve ligation neuropathic pain model.
Subject(s)
Analgesics/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Pain/drug therapy , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Analgesics/chemistry , Analgesics/pharmacology , Animals , Area Under Curve , Chronic Disease , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , Indazoles/pharmacology , Morpholines/chemical synthesis , Morpholines/chemistry , Morpholines/pharmacology , Peripheral Nervous System Diseases/drug therapy , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Isosteric replacement of the urea group of lead compound 1 led to novel substituted piperidine phenylamide analogues. SAR on the electron-induced effects of various linkers as well as substituents on the phenyl rings and the piperidine nitrogen has been investigated. Many single-digit nanomolar MCH R1 antagonists have been identified from this series.
Subject(s)
Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, Pituitary Hormone/antagonists & inhibitors , Humans , Structure-Activity RelationshipABSTRACT
Biaryl urea lead compound 1 was discovered earlier in our MCH antagonist program. Novel benzimidazole analogues with increased chemical stability, devoid of the potential carcinogenic liability associated with a biarylamine moiety, were synthesized and evaluated to be potent MCH R1 antagonists. Two compounds in this series have demonstrated in vivo efficacy in a rodent obesity model.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Body Weight/drug effects , Receptors, Pituitary Hormone/antagonists & inhibitors , Administration, Oral , Animals , Disease Models, Animal , Drug Design , Rats , Structure-Activity RelationshipABSTRACT
Benzazepines 1 and 2 (SCH 23390 and SCH 39166, respectively) are two classical benzazepine D1/D5 antagonists, with Ki values 1.4 and 1.2 nM, respectively. Compound 2 has been in human clinical trials for a variety of diseases, including schizophrenia, cocaine addition, and obesity. Both 1 and 2 displayed low plasma levels and poor oral bioavailability, due to rapid first-pass metabolism of the phenol moieties. Several heterocyclic systems containing an N-H hydrogen bond donor were synthesized and evaluated as phenol isosteres. The preference orientation of the hydrogen bond was established by comparison of analogues containing different NH vectors. Replacement of the phenol group of 2 with an indole ring generated the first potent D1/D5 antagonist 11b. Further optimization led to the synthesis of very potent benzimidazolones 19, 20 and benzothiazolone analogues 28, 29. These compounds have excellent selectivity over D2-D4 receptors, alpha2a receptor, and the 5-HT transporter. Compared to 2, these heterocyclic phenol isosteres showed much better pharmacokinetic profiles as demonstrated by rat plasma levels. In sharp contrast, similar phenolic replacements in 1 decreased the binding affinity dramatically, presumably due to a conformational change of the pendant phenyl group. However, one indazole compound 33 was identified as a potent D1/D5 ligand in this series.
Subject(s)
Benzazepines/chemical synthesis , Dopamine Antagonists/chemical synthesis , Phenols/chemical synthesis , Receptors, Dopamine D1/antagonists & inhibitors , Animals , Benzazepines/pharmacokinetics , Benzazepines/pharmacology , Cell Line , Cricetinae , Cricetulus , Cyclic AMP/biosynthesis , Dopamine Antagonists/pharmacokinetics , Dopamine Antagonists/pharmacology , Drug Design , Male , Models, Molecular , Phenols/pharmacokinetics , Phenols/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D5 , Structure-Activity RelationshipABSTRACT
A series of aminoalkylazetidines has been discovered as novel ORL1 receptor ligands. Structure-activity relationships have been investigated at the azetidine N and the alkyl side chain sites. Several potent and selective analogues have been identified.
