ABSTRACT
Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aß levels in rats and nonhuman primates and CSF Aß levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Protein Precursor/antagonists & inhibitors , Cyclic S-Oxides/pharmacology , Drug Discovery , Thiadiazines/pharmacology , Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Cyclic S-Oxides/chemical synthesis , Cyclic S-Oxides/chemistry , Dogs , Dose-Response Relationship, Drug , Humans , Macaca fascicularis , Models, Molecular , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiadiazines/chemical synthesis , Thiadiazines/chemistryABSTRACT
This patent review covers the contents of Hoffman-La Roche and Siena Biotech's patent application WO2012156284 titled '1,3-Oxazines as BACE1 and/or BACE2 Inhibitors.' Beta-site amyloid precursor protein-converting enzyme (BACE1) and BACE2 activities are reported to support the claimed compounds' use as therapeutics for Alzheimer's disease and type II diabetes, respectively. A common core motif of the claimed compounds is the six-membered 1,3-oxazine system. To gain access to the S3 and S3 subpocket of the BACE1 active site, various linkers are described including nitrogen- and oxygen-based, aryl, and amide-based linkers. Of the 65 compounds claimed, 6 had IC50s less than 100 nM in the BACE1 cell assay. Cellular BACE2 inhibition data are reported for 20 compounds with 2 under 100 nM.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Oxazines/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/physiopathology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/physiopathology , Drug Design , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Inhibitory Concentration 50 , Oxazines/administration & dosage , Oxazines/chemistry , Patents as TopicABSTRACT
Inhibition of BACE1 to prevent brain Aß peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aß levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aß40 levels when administered orally to rats.
ABSTRACT
The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.
Subject(s)
Receptor, Cannabinoid, CB2/antagonists & inhibitors , Sulfonamides/chemical synthesis , Sulfones/chemistry , Sulfones/chemical synthesis , Animals , Calcium Channels/metabolism , Cytochrome P-450 Enzyme System , Drug Inverse Agonism , Humans , Piperidines/chemistry , Rats , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Sulfones/pharmacokineticsABSTRACT
Rebeccamycin and staurosporine represent two broad classes of indolocarbazole glycoside natural products with antitumor properties. Based upon previous sequence annotation and in vivo studies, rebG encodes for the rebeccamycin N-glucosyltransferase, and rebM for the requisite 4'-O-methyltransferase. In the current study, an efficient in vivo biotransformation system for RebG was established in both Streptomyces lividans and Escherichia coli. Bioconversion experiments revealed RebG to glucosylate a set of indolocarbazole surrogates, the products of which could be further modified by in vitro RebM-catalyzed 4'-O-methylation. Both RebG and RebM displayed substrate promiscuity, and evidence for a remarkable lack of RebG regioselectivity in the presence of asymmetric substrates is also provided. In the context of the created indolocarbazole analogues, cytotoxicity assays also highlight the importance of 4'-O-methylation for their biological activity.
Subject(s)
Bacterial Proteins/chemistry , Carbazoles/chemical synthesis , Glucosyltransferases/chemistry , Indoles/chemistry , Methyltransferases/chemistry , Carbazoles/chemistry , Catalysis , Cell Line, Tumor , Dose-Response Relationship, Drug , Glycosylation , Humans , In Vitro Techniques , Molecular Structure , Time Factors , Tumor Cells, CulturedABSTRACT
Bipiperidine amide 1 has been identified as a CC chemokine receptor 3 (CCR3) antagonist. Optimization of its structure-activity relationship has resulted in the identification of cis (R,R)-4-[(3,4-dichlorophenyl)methyl]-3-hydroxymethyl-1'(6-quinolinylcarbonyl)-1,4'-bipiperidine 14n, which exhibits potent receptor affinity and inhibition of both calcium flux and eosinophil chemotaxis.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Animals , Humans , Molecular Structure , Receptors, CCR3 , Structure-Activity RelationshipABSTRACT
Recent studies of peptide dimers linked by Trp-Trp (ditryptophan) crosslinks suggest that the crosslinks can reinforce antiparallel beta-structure. Depending on environment, gramicidins A, B and C form either helical ion channels with parallel beta-structure or non-functional pores with antiparallel beta-structure. In the channel conformation of the gramicidins Trp9 and Trp15 are close in space, but in the pore conformation Trp9 and Trp15 are far apart. We hypothesized that a ditryptophan crosslink between Trp9 and Trp15 could pre-organize gramicidin in an active conformation. To test the potential for preorganization, an intramolecular ditryptophan crosslink was formed between Trp9 and Trp15 in a W13F mutant of gramicidin B. Photooxidative conditions were shown to generate ditryptophan crosslinks in low yields. While not preparatively useful, photooxidative tryptophan crosslinking may have implications for protein aging processes like cataract formation. The ditryptophan crosslink in the gramicidin B mutant substantially lowered the antibiotic activity of the gramicidin B mutant, unlike the ditryptophan crosslink in the antibiotic X-indolicidin. The biaryl chromophore generated diagnostic Cotton effects in the CD spectrum that revealed the absolute stereochemistry of the biaryl chromophore, but the biaryl chromophore obscured diagnostic features below 220 nm. However, changes in peptide conformation were reflected in changes in the biaryl region of the CD spectrum above 240 nm.
Subject(s)
Gramicidin/chemical synthesis , Gramicidin/metabolism , Tryptophan/metabolism , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Bacteria/metabolism , Circular Dichroism , Cross-Linking Reagents , Gramicidin/pharmacology , Mutation , Photochemistry , Protein ConformationABSTRACT
Indolocarbazole glycosides are balanced between two conformations: a "closed" conformation containing a cyclic hydrogen bond between the indolocarbazole NH and the pyranose oxygen and an "open" conformation in which the indolocarbazole NH is hydrogen bonded to solvent. The open conformation never has a commanding advantage, even in DMSO, but in nonpolar environments the cyclic conformation predominates.