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1.
J Pharmacol Exp Ther ; 374(2): 252-263, 2020 08.
Article in English | MEDLINE | ID: mdl-32493725

ABSTRACT

Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis. These findings suggest that OGA inhibition may reduce tau pathology in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be critical to understand the physiologic and toxicological consequences of chronic O-GlcNAc elevation in vivo. SIGNIFICANCE STATEMENT: MK-8719 is a novel, selective, and potent O-linked N-acetylglucosamine (O-GlcNAc)-ase (OGA) inhibitor that inhibits OGA enzyme activity across multiple species with comparable in vitro potency. In vivo, MK-8719 elevates brain O-GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of Alzheimer disease and other tauopathies.


Subject(s)
Enzyme Inhibitors/pharmacology , Tauopathies/drug therapy , Tauopathies/metabolism , beta-N-Acetylhexosaminidases/antagonists & inhibitors , tau Proteins/metabolism , Animals , Atrophy/drug therapy , Brain/drug effects , Brain/metabolism , Brain/pathology , Disease Models, Animal , Enzyme Inhibitors/therapeutic use , Locomotion/drug effects , Male , Mice , PC12 Cells , Rats , Tauopathies/pathology , Tauopathies/physiopathology
2.
J Med Chem ; 62(22): 10062-10097, 2019 11 27.
Article in English | MEDLINE | ID: mdl-31487175

ABSTRACT

Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chemistry and pharmacological studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clinical trials.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , beta-N-Acetylhexosaminidases/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Brain/drug effects , Dogs , Drug Discovery , Enzyme Inhibitors/blood , Enzyme Inhibitors/pharmacokinetics , Humans , Macaca mulatta , Male , PC12 Cells , Rats , Rats, Wistar , Structure-Activity Relationship , Tauopathies/drug therapy , beta-N-Acetylhexosaminidases/chemistry , beta-N-Acetylhexosaminidases/metabolism
3.
Mol Neurodegener ; 12(1): 39, 2017 05 18.
Article in English | MEDLINE | ID: mdl-28521765

ABSTRACT

BACKGROUND: Hyperphosphorylation of microtubule-associated protein tau is a distinct feature of neurofibrillary tangles (NFTs) that are the hallmark of neurodegenerative tauopathies. O-GlcNAcylation is a lesser known post-translational modification of tau that involves the addition of N-acetylglucosamine onto serine and threonine residues. Inhibition of O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc modification, has been shown to reduce tau pathology in several transgenic models. Clarifying the underlying mechanism by which OGA inhibition leads to the reduction of pathological tau and identifying translatable measures to guide human dosing and efficacy determination would significantly facilitate the clinical development of OGA inhibitors for the treatment of tauopathies. METHODS: Genetic and pharmacological approaches are used to evaluate the pharmacodynamic response of OGA inhibition. A panel of quantitative biochemical assays is established to assess the effect of OGA inhibition on pathological tau reduction. A "click" chemistry labeling method is developed for the detection of O-GlcNAcylated tau. RESULTS: Substantial (>80%) OGA inhibition is required to observe a measurable increase in O-GlcNAcylated proteins in the brain. Sustained and substantial OGA inhibition via chronic treatment with Thiamet G leads to a significant reduction of aggregated tau and several phosphorylated tau species in the insoluble fraction of rTg4510 mouse brain and total tau in cerebrospinal fluid (CSF). O-GlcNAcylated tau is elevated by Thiamet G treatment and is found primarily in the soluble 55 kD tau species, but not in the insoluble 64 kD tau species thought as the pathological entity. CONCLUSION: The present study demonstrates that chronic inhibition of OGA reduces pathological tau in the brain and total tau in the CSF of rTg4510 mice, most likely by directly increasing O-GlcNAcylation of tau and thereby maintaining tau in the soluble, non-toxic form by reducing tau aggregation and the accompanying panoply of deleterious post-translational modifications. These results clarify some conflicting observations regarding the effects and mechanism of OGA inhibition on tau pathology, provide pharmacodynamic tools to guide human dosing and identify CSF total tau as a potential translational biomarker. Therefore, this study provides additional support to develop OGA inhibitors as a treatment for Alzheimer's disease and other neurodegenerative tauopathies.


Subject(s)
Tauopathies/metabolism , beta-N-Acetylhexosaminidases/antagonists & inhibitors , tau Proteins/metabolism , Animals , Mice , Mice, Transgenic , Protein Processing, Post-Translational , Pyrans/pharmacology , Thiazoles/pharmacology
4.
Nat Chem Biol ; 13(6): 613-615, 2017 06.
Article in English | MEDLINE | ID: mdl-28346407

ABSTRACT

O-GlcNAc hydrolase (OGA) catalyzes removal of ßα-linked N-acetyl-D-glucosamine from serine and threonine residues. We report crystal structures of Homo sapiens OGA catalytic domain in apo and inhibited states, revealing a flexible dimer that displays three unique conformations and is characterized by subdomain α-helix swapping. These results identify new structural features of the substrate-binding groove adjacent to the catalytic site and open new opportunities for structural, mechanistic and drug discovery activities.


Subject(s)
Models, Biological , beta-N-Acetylhexosaminidases/chemistry , beta-N-Acetylhexosaminidases/metabolism , Acetylglucosamine/metabolism , Binding Sites , Calorimetry , Catalytic Domain , Crystallography, X-Ray , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Humans , Protein Structure, Tertiary , Substrate Specificity
5.
J Med Chem ; 59(10): 4778-89, 2016 05 26.
Article in English | MEDLINE | ID: mdl-27088900

ABSTRACT

Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark of several neurodegenerative diseases including Alzheimer's disease. In vivo detection of NFTs using PET imaging represents a unique opportunity to develop a pharmacodynamic tool to accelerate the discovery of new disease modifying therapeutics targeting tau pathology. Herein, we present the discovery of 6-(fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine, 6 ([(18)F]-MK-6240), as a novel PET tracer for detecting NFTs. 6 exhibits high specificity and selectivity for binding to NFTs, with suitable physicochemical properties and in vivo pharmacokinetics.


Subject(s)
Drug Discovery , Isoquinolines/chemistry , Molecular Imaging , Neurofibrillary Tangles/pathology , Positron-Emission Tomography , Fluorine Radioisotopes/chemistry , Humans , Isoquinolines/chemical synthesis , Isoquinolines/pharmacokinetics , Molecular Structure , Neurofibrillary Tangles/metabolism
6.
Bioorg Med Chem Lett ; 25(21): 4777-4781, 2015 Nov 01.
Article in English | MEDLINE | ID: mdl-26231160

ABSTRACT

In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 µM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold).


Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Migraine Disorders/drug therapy , Oxazolidinones/pharmacology , Oxazolidinones/therapeutic use , Animals , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Rats , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 25(21): 4812-4819, 2015 Nov 01.
Article in English | MEDLINE | ID: mdl-26195137

ABSTRACT

The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 µM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Hydantoins/chemistry , Hydantoins/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Hydantoins/chemical synthesis , Methylation , Models, Molecular , Molecular Structure , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 24(1): 258-61, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24332093

ABSTRACT

A new class of CGRP receptor antagonists was identified by replacing the central amide of a previously identified anilide lead structure with ethylene, ethane, or ethyne linkers. (E)-Alkenes as well as alkynes were found to preserve the proper bioactive conformation of the amides, necessary for efficient receptor binding. Further exploration resulted in several potent compounds against CGRP-R with low susceptibility to P-gp mediated efflux.


Subject(s)
Alkenes/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Alkenes/chemical synthesis , Alkenes/chemistry , Amides/chemistry , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Molecular Structure , Structure-Activity Relationship
9.
J Pharmacol Exp Ther ; 347(2): 478-86, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23975906

ABSTRACT

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide whose agonist interaction with the CGRP receptor (CGRP-R) in the periphery promotes vasodilation, neurogenic inflammation and trigeminovascular sensory activation. This process is implicated in the cause of migraine headaches, and CGRP-R antagonists in clinical development have proven effective in treating migraine-related pain in humans. CGRP-R is expressed on blood vessel smooth muscle and sensory trigeminal neurons and fibers in the periphery as well as in the central nervous system. However, it is not clear what role the inhibition of central CGRP-R plays in migraine pain relief. To this end, the CGRP-R positron emission tomography (PET) tracer [(11)C]MK-4232 (2-[(8R)-8-(3,5-difluorophenyl)-6,8-[6-(11)C]dimethyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-[(2R)-2'-oxospiro[1,3-dihydroindene-2,3'-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide) was discovered and developed for use in clinical PET studies. In rhesus monkeys and humans, [(11)C]MK-4232 displayed rapid brain uptake and a regional brain distribution consistent with the known distribution of CGRP-R. Monkey PET studies with [(11)C]MK-4232 after intravenous dosing with CGRP-R antagonists validated the ability of [(11)C]MK-4232 to detect changes in CGRP-R occupancy in proportion to drug plasma concentration. Application of [(11)C]MK-4232 in human PET studies revealed that telcagepant achieved only low receptor occupancy at an efficacious dose (140 mg PO). Therefore, it is unlikely that antagonism of central CGRP-R is required for migraine efficacy. However, it is not known whether high central CGRP-R antagonism may provide additional therapeutic benefit.


Subject(s)
Acetanilides/pharmacokinetics , Analgesics/pharmacokinetics , Azepines/pharmacokinetics , Brain/metabolism , Calcitonin Gene-Related Peptide Receptor Antagonists , Imidazoles/pharmacokinetics , Positron-Emission Tomography/methods , Radiopharmaceuticals/pharmacokinetics , Spiro Compounds/pharmacokinetics , Acetanilides/chemistry , Adult , Analgesics/therapeutic use , Animals , Azepines/therapeutic use , Brain/diagnostic imaging , Carbon Radioisotopes , Female , Humans , Imidazoles/therapeutic use , Macaca mulatta , Male , Middle Aged , Migraine Disorders/drug therapy , Migraine Disorders/metabolism , Molecular Structure , Protein Binding , Radiopharmaceuticals/chemistry , Species Specificity , Spiro Compounds/chemistry , Tissue Distribution , Young Adult
10.
ACS Med Chem Lett ; 4(9): 863-8, 2013 Sep 12.
Article in English | MEDLINE | ID: mdl-24900761

ABSTRACT

Rational modification of the potent calcitonin gene-related peptide (CGRP) receptor antagonist MK-3207 led to a series of analogues with enhanced CNS penetrance and a convenient chemical handle for introduction of a radiolabel. A number of (11)C-tracers were synthesized and evaluated in vivo, leading to the identification of [(11)C]8 ([(11)C]MK-4232), the first positron emission tomography tracer for the CGRP receptor.

11.
Bioorg Med Chem Lett ; 22(12): 3941-5, 2012 Jun 15.
Article in English | MEDLINE | ID: mdl-22607672

ABSTRACT

Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.


Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Migraine Disorders/drug therapy , Pyridines/chemical synthesis , Pyridines/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Administration, Oral , Analgesics/blood , Animals , Biological Availability , Disease Models, Animal , Dogs , Humans , Macaca mulatta , Mice , Pyridines/blood , Rats , Receptors, Calcitonin Gene-Related Peptide/metabolism , Species Specificity , Spiro Compounds/blood
12.
Bioorg Med Chem Lett ; 21(9): 2683-6, 2011 May 01.
Article in English | MEDLINE | ID: mdl-21251825

ABSTRACT

In our ongoing efforts to develop CGRP receptor antagonists for the treatment of migraine, we aimed to improve upon telecagepant by targeting a compound with a lower projected clinical dose. Imidazoazepanes were identified as potent caprolactam replacements and SAR of the imidazole yielded the tertiary methyl ether as an optimal substituent for potency and hERG selectivity. Combination with the azabenzoxazinone spiropiperidine ultimately led to preclinical candidate 30 (MK-2918).


Subject(s)
Azepines/chemical synthesis , Calcitonin Gene-Related Peptide Receptor Antagonists , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Analgesics, Non-Narcotic/chemical synthesis , Analgesics, Non-Narcotic/chemistry , Analgesics, Non-Narcotic/pharmacology , Animals , Azepines/chemistry , Azepines/pharmacology , Biological Availability , Caprolactam/chemistry , Cells, Cultured , Dogs , Humans , Imidazoles/chemistry , Inhibitory Concentration 50 , Macaca mulatta , Migraine Disorders/drug therapy , Molecular Structure , Rats , Structure-Activity Relationship
13.
Bioorg Med Chem Lett ; 20(22): 6827-30, 2010 Nov 15.
Article in English | MEDLINE | ID: mdl-20850973

ABSTRACT

A previously utilized quinoline-for-N-phenylamide replacement strategy was employed against a central amide in a novel class of CGRP receptor antagonists. A unique and unexpected substitution pattern was ultimately required to maintain reasonable affinity for the CGRP receptor, while at the same time predicting acceptable heterocycle positioning for related analogs. Subsequently, specific quinoline and naphthyridine compounds were prepared which supported these structural predictions by displaying CGRP binding affinities in the 0.037-0.15 nM range.


Subject(s)
Amides/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Amides/chemistry , Stereoisomerism
14.
Bioorg Med Chem Lett ; 20(8): 2572-6, 2010 Apr 15.
Article in English | MEDLINE | ID: mdl-20299218

ABSTRACT

A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K(i)=23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K(i)=0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species.


Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Quinolines/pharmacology , Animals , Biological Availability , Dogs , Drug Evaluation, Preclinical , Macaca mulatta , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats
15.
Bioorg Med Chem Lett ; 20(6): 1885-9, 2010 Mar 15.
Article in English | MEDLINE | ID: mdl-20176482

ABSTRACT

The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pK(a) of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Alphabeta production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.


Subject(s)
Amines/metabolism , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid/metabolism , Enzyme Inhibitors/pharmacology , Catalysis , Humans , Models, Molecular , Structure-Activity Relationship
16.
J Pharmacol Exp Ther ; 333(1): 152-60, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20065019

ABSTRACT

Calcitonin gene-related peptide (CGRP) has long been hypothesized to play a key role in migraine pathophysiology, and the advent of small-molecule antagonists has clearly demonstrated a clinical link between blocking the CGRP receptor and migraine efficacy. 2-[(8R)-8-(3,5-Difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) represents the third CGRP receptor antagonist to display clinical efficacy in migraine trials. Here, we report the pharmacological characterization of MK-3207, a potent and orally bioavailable CGRP receptor antagonist. In vitro, MK-3207 is a potent antagonist of the human and rhesus monkey CGRP receptors (K(i) = 0.024 nM). In common with other CGRP receptor antagonists, MK-3207 displays lower affinity for CGRP receptors from other species, including canine and rodent. As a consequence of species selectivity, the in vivo potency was assessed in a rhesus monkey pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging. MK-3207 produced a concentration-dependent inhibition of dermal vasodilation, with plasma concentrations of 0.8 and 7 nM required to block 50 and 90% of the blood flow increase, respectively. The tritiated analog [3H]MK-3207 was used to study the binding characteristics on the human CGRP receptor. [3H]MK-3207 displayed reversible and saturable binding (K(D) = 0.06 nM), and the off-rate was determined to be 0.012 min(-1), with a t(1/2) value of 59 min. In vitro autoradiography studies on rhesus monkey brain slices identified the highest level of binding in the cerebellum, brainstem, and meninges. Finally, as an index of central nervous system penetrability, the in vivo cerebrospinal fluid/plasma ratio was determined to be 2 to 3% in cisterna magna-ported rhesus monkeys.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Spiro Compounds/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Autoradiography , Binding, Competitive , Biological Transport , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/blood , Bridged Bicyclo Compounds, Heterocyclic/cerebrospinal fluid , Cell Line , Chlorocebus aethiops , Female , Humans , Kinetics , Macaca mulatta , Male , Mice , Radioligand Assay , Receptors, Adrenomedullin , Receptors, Calcitonin/metabolism , Receptors, Calcitonin Gene-Related Peptide/physiology , Receptors, Islet Amyloid Polypeptide , Receptors, Peptide/metabolism , Spiro Compounds/blood , Spiro Compounds/cerebrospinal fluid , Vasodilation/drug effects
17.
ACS Med Chem Lett ; 1(1): 24-9, 2010 Apr 08.
Article in English | MEDLINE | ID: mdl-24900170

ABSTRACT

Incorporation of polar functionality into a series of highly potent calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort to improve pharmacokinetics. This strategy identified piperazinone analogues that possessed improved solubility at acidic pH and increased oral bioavailability in monkeys. Further optimization led to the discovery of the clinical candidate 2-[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) (4), the most potent orally active CGRP receptor antagonist described to date.

18.
Bioorg Med Chem Lett ; 19(19): 5787-90, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19703767

ABSTRACT

A novel class of CGRP receptor antagonists was rationally designed by modifying a highly potent, but structurally complex, CGRP receptor antagonist. Initial modifications focused on simplified structures, with increased flexibility. Subsequent to the preparation of a less-potent but more flexible lead, classic medicinal chemistry methods were applied to restore high affinity (compound 22, CGRP Ki=0.035 nM) while maintaining structural diversity relative to the lead. Good selectivity against the closely related adrenomedullin-2 receptor was also achieved.


Subject(s)
Acetamides/chemistry , Calcitonin Gene-Related Peptide Receptor Antagonists , Spiro Compounds/chemistry , Acetamides/chemical synthesis , Acetamides/pharmacology , Animals , Cell Line , Drug Design , Humans , Rats , Receptors, Calcitonin Gene-Related Peptide/metabolism , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Structure-Activity Relationship
19.
J Pharmacol Exp Ther ; 328(1): 131-40, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18854490

ABSTRACT

beta-Site amyloid precursor protein (APP)-cleaving enzyme (BACE) 1 cleavage of amyloid precursor protein is an essential step in the generation of the potentially neurotoxic and amyloidogenic A beta 42 peptides in Alzheimer's disease. Although previous mouse studies have shown brain A beta lowering after BACE1 inhibition, extension of such studies to nonhuman primates or man was precluded by poor potency, brain penetration, and pharmacokinetics of available inhibitors. In this study, a novel tertiary carbinamine BACE1 inhibitor, tertiary carbinamine (TC)-1, was assessed in a unique cisterna magna ported rhesus monkey model, where the temporal dynamics of A beta in cerebrospinal fluid (CSF) and plasma could be evaluated. TC-1, a potent inhibitor (IC(50) approximately 0.4 nM), has excellent passive membrane permeability, low susceptibility to P-glycoprotein transport, and lowered brain A beta levels in a mouse model. Intravenous infusion of TC-1 led to a significant but transient lowering of CSF and plasma A beta levels in conscious rhesus monkeys because it underwent CYP3A4-mediated metabolism. Oral codosing of TC-1 with ritonavir, a potent CYP3A4 inhibitor, twice daily over 3.5 days in rhesus monkeys led to sustained plasma TC-1 exposure and a significant and sustained reduction in CSF sAPP beta, A beta 40, A beta 42, and plasma A beta 40 levels. CSF A beta 42 lowering showed an EC(50) of approximately 20 nM with respect to the CSF [TC-1] levels, demonstrating excellent concordance with its potency in a cell-based assay. These results demonstrate the first in vivo proof of concept of CSF A beta lowering after oral administration of a BACE1 inhibitor in a nonhuman primate.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Protein Precursor/cerebrospinal fluid , Amyloid beta-Protein Precursor/antagonists & inhibitors , Animals , Aspartic Acid Endopeptidases/antagonists & inhibitors , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Humans , Infusions, Intravenous , Macaca mulatta , Mice , Mice, Transgenic , Transfection
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