ABSTRACT
The c-MYC oncogene transcription factor has been implicated in cell cycle regulation controlling cell growth and proliferation. It is tightly regulated in normal cells, but has been shown to be deregulated in cancer cells, and is thus an attractive target for oncogenic therapies. Building upon previous SAR, a series of analogues containing benzimidazole core replacements were prepared and evaluated, leading to the identification of imidazopyridazine compounds that were shown to possess equivalent or improved c-MYC HTRF pEC50 values, lipophilicity, solubility, and rat pharmacokinetics. The imidazopyridazine core was therefore determined to be superior to the original benzimidazole core and a viable alternate for continued lead optimization and medicinal chemistry campaigns.
Subject(s)
Aminopyridines , Proto-Oncogene Proteins c-myc , Rats , Animals , Proto-Oncogene Proteins c-myc/metabolism , Gene Expression Regulation , Transcription Factors/metabolism , BenzimidazolesABSTRACT
E1A binding protein (p300) and CREB binding protein (CBP) are two highly homologous and multidomain histone acetyltransferases. These two proteins are involved in many cellular processes by acting as coactivators of a large number of transcription factors. Dysregulation of p300/CBP has been found in a variety of cancers and other diseases, and inhibition has been shown to decrease Myc expression. Herein, we report the identification of a series of highly potent, proline-based small-molecule p300/CBP histone acetyltransferase (HAT) inhibitors using DNA-encoded library technology in combination with high-throughput screening. The strategy of reducing ChromlogD and fluorination of metabolic soft spots was explored to improve the pharmacokinetic properties of potent p300 inhibitors. Fluorination of both cyclobutyl and proline rings of 22 led to not only reduced clearance but also improved cMyc cellular potency.
Subject(s)
CREB-Binding Protein , High-Throughput Screening Assays , Proline , Histone Acetyltransferases , Adenovirus E1A Proteins/metabolism , p300-CBP Transcription Factors , DNA , TechnologyABSTRACT
Elevated expression of the c-MYC oncogene is one of the most common abnormalities in human cancers. Unfortunately, efforts to identify pharmacological inhibitors that directly target MYC have not yet yielded a drug-like molecule due to the lack of any known small molecule binding pocket in the protein, which could be exploited to disrupt MYC function. We have recently described a strategy to target MYC indirectly, where a screening effort designed to identify compounds that can rapidly decrease endogenous c-MYC protein levels in a MYC-amplified cell line led to the discovery of a compound series that phenocopies c-MYC knockdown by siRNA. Herein, we describe our medicinal chemistry program that led to the discovery of potent, orally bioavailable c-MYC-reducing compounds. The development of a minimum pharmacophore model based on empirical structure activity relationship as well as the property-based approach used to modulate pharmacokinetics properties will be highlighted.
Subject(s)
Drug Discovery , Proto-Oncogene Proteins c-myc/metabolism , Small Molecule Libraries/pharmacology , Animals , Area Under Curve , Cell Line, Tumor , Half-Life , Humans , Proto-Oncogene Proteins c-myc/genetics , Rats , Small Molecule Libraries/pharmacokinetics , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Identification of ligands that selectively activate the M1 muscarinic signaling pathway has been sought for decades to treat a range of neurological and cognitive disorders. Herein, we describe the optimization efforts focused on addressing key physicochemical and safety properties, ultimately leading to the clinical candidate MK-7622, a highly selective positive allosteric modulator of the M1 muscarinic receptor that has entered Phase II studies in patients with Alzheimer's disease.
ABSTRACT
Developing new antiretroviral therapies for HIV-1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethylâ (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand-transfer inhibitor approved for the treatment of HIV infection with twice-daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK-8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug-drug interaction profile of raltegravir.
Subject(s)
HIV Integrase Inhibitors/chemistry , Oxadiazoles/chemistry , Prodrugs/chemistry , Pyrimidinones/chemistry , Pyrrolidinones/chemistry , Acetals/chemistry , Animals , Area Under Curve , Carbonates/chemistry , Dogs , Drug Evaluation, Preclinical , HIV Integrase/chemistry , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacokinetics , HIV-1/enzymology , Half-Life , Hepatocytes/metabolism , Humans , Intestinal Mucosa/metabolism , Male , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacokinetics , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , ROC Curve , Raltegravir Potassium , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Analogs of the dual orexin receptor antagonist filorexant were prepared. Replacement of the ether linkage proved highly sensitive toward modification with an acetylene linkage providing compounds with the best in vitro and in vivo potency profiles.
Subject(s)
Acetylene/chemistry , Orexin Receptor Antagonists , Piperidines/pharmacology , Pyrimidines/pharmacology , Animals , Dose-Response Relationship, Drug , Mice , Mice, Knockout , Molecular Structure , Orexin Receptors/deficiency , Orexin Receptors/metabolism , Piperidines/chemical synthesis , Piperidines/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
A series of methoxynaphthalene amides were prepared and evaluated as alternatives to quinolizidinone amide M1 positive allosteric modulators. A methoxy group was optimal for M1 activity and addressed key P-gp issues present in the aforementioned quinolizidinone amide series.
Subject(s)
Amides/chemistry , Naphthalenes/chemistry , Quinolizidines/chemistry , Receptor, Muscarinic M1/metabolism , Allosteric Regulation , Amides/chemical synthesis , Amides/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Mice , Protein Binding , Receptor, Muscarinic M1/chemistry , Structure-Activity RelationshipABSTRACT
A series of benzothiophene methyl amines were examined in an effort to identify non-amidine chemotypes with reduced polypharmacology from existing leads with the goal of finding potent ASIC3 channel blockers to advance the therapeutic evaluation of ASIC3 inhibition.
Subject(s)
Nerve Tissue Proteins/antagonists & inhibitors , Sodium Channel Blockers/chemistry , Acid Sensing Ion Channels , Amidines/chemistry , Amiloride/chemistry , Animals , Nerve Tissue Proteins/metabolism , Rats , Sodium Channel Blockers/pharmacology , Sodium Channels/metabolism , Structure-Activity RelationshipABSTRACT
One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M(1) muscarinic receptor. A number of nonselective M(1) muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M(2) to M(5) subtypes. One strategy to confer selectivity for M(1) is the identification of positive allosteric modulators, which would target an allosteric site on the M(1) receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have been previously identified as highly selective M(1) positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.
Subject(s)
Cholinergic Agents/chemical synthesis , Nitriles/chemical synthesis , Nootropic Agents/chemical synthesis , Piperidines/chemical synthesis , Quinolizidines/chemical synthesis , Quinolizines/chemical synthesis , Receptor, Muscarinic M1/physiology , Allosteric Regulation , Animals , Biological Availability , CHO Cells , Cholinergic Agents/chemistry , Cholinergic Agents/pharmacology , Cricetinae , Cricetulus , Fear/drug effects , Humans , Male , Mice , Nitriles/chemistry , Nitriles/pharmacology , Nootropic Agents/chemistry , Nootropic Agents/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Quinolizidines/chemistry , Quinolizidines/pharmacology , Quinolizines/chemistry , Quinolizines/pharmacology , Structure-Activity RelationshipABSTRACT
SAR study of the piperidine moiety in a series of quinolizidinone carboxylic acid M(1) positive allosteric modulators was examined. While the SAR was generally flat, compounds were identified with high CNS exposure to warrant additional in vivo evaluation.
Subject(s)
Piperidines/pharmacology , Allosteric Regulation , Animals , CHO Cells , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Piperidines/metabolism , Structure-Activity RelationshipABSTRACT
Fused aromatics such as naphthalene were identified as highly potent and CNS penetrant M(1) positive allosteric modulators during an SAR study to replace the phenyl B-ring linkage.
Subject(s)
Naphthols/chemistry , Receptor, Muscarinic M1/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/blood , ATP Binding Cassette Transporter, Subfamily B, Member 1/cerebrospinal fluid , Allosteric Regulation/drug effects , Animals , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Humans , Molecular Structure , Naphthols/pharmacology , Quinolones/chemistry , Quinolones/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
The phenyl ring in a series of quinolone carboxylic acid M(1) positive allosteric modulators was replaced with a variety of heterocycles in order to reduce protein plasma binding and enhance CNS exposure.
Subject(s)
Carboxylic Acids/pharmacology , Heterocyclic Compounds/pharmacology , Pyridones/chemistry , Allosteric Regulation , Animals , Blood Proteins/chemistry , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacokinetics , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacokinetics , Humans , RatsABSTRACT
Replacement of a phenyl ring with N-linked heterocycles in a series of quinolone carboxylic acid M1 positive allosteric modulators was investigated. In particular, a pyrazole derivative exhibited improvements in potency, free fraction, and CNS exposure.
Subject(s)
Carboxylic Acids/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Pyrazoles/chemical synthesis , Quinolines/chemical synthesis , Allosteric Regulation , Animals , CHO Cells , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Cell Line , Cricetinae , Cricetulus , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Molecular Structure , Pyrazoles/chemistry , Pyrazoles/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Incorporation of pyridines and diazines into the biphenyl region of quinolone carboxylic acid derived M(1) positive allosteric modulators was investigated as a means of lowering plasma protein binding to enhance CNS exposure.
Subject(s)
Blood Proteins/chemistry , Pyridines/chemistry , Receptor, Muscarinic M1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Allosteric Regulation , Animals , Blood Proteins/metabolism , Humans , Protein Binding , Pyridines/chemical synthesis , Pyridines/pharmacology , Rats , Receptor, Muscarinic M1/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis, structure-activity relationship (SAR), and pharmacological evaluation of analogs of the acid-sensing ion channel (ASIC) inhibitor A-317567 are reported. It was found that the compound with an acetylenic linkage was the most potent ASIC-3 channel blocker. This compound reversed mechanical hypersensitivity in the rat iodoacetate model of osteoarthritis pain, although sedation was noted. Sedation was also observed in ASIC-3 knockout mice, questioning whether sedation and antinociception are mediated via a non-ASIC-3 specific mechanism.
Subject(s)
Acid Sensing Ion Channel Blockers/chemical synthesis , Acid Sensing Ion Channel Blockers/pharmacology , Acid Sensing Ion Channels/drug effects , Analgesics/chemical synthesis , Analgesics/pharmacology , Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Naphthalenes/chemical synthesis , Naphthalenes/pharmacology , Acid Sensing Ion Channels/biosynthesis , Animals , Behavior, Animal/drug effects , Electrophysiological Phenomena , Freund's Adjuvant , Iodoacetates , Male , Mice , Neurons/drug effects , Neurons/metabolism , Osteoarthritis/chemically induced , Osteoarthritis/drug therapy , Pain/chemically induced , Pain/drug therapy , Pain Measurement/drug effects , Physical Stimulation , Postural Balance/drug effects , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Positive allosteric modulation of the M1 muscarinic receptor represents an approach to treat the cognitive decline in patients with Alzheimer's disease. Replacement of a quinolone ring system in a quinolone carboxylic acid series of M1 modulators with a quinolizidinone bearing a basic amine linkage led to a series of compounds with higher free fraction, enhanced CNS exposure, and improved efficacy in rodent in vivo models of cognition.
ABSTRACT
A series of indole amidines modified at the 2-position of the indole ring were evaluated as inhibitors of Acid-Sensing Ion Channel-3 (ASIC3), a novel target for the treatment of chronic pain.
Subject(s)
Amidines/chemistry , Chemistry, Pharmaceutical/methods , Sodium Channels/chemistry , Acid Sensing Ion Channels , Animals , Drug Design , Electrophysiology , Indoles/chemistry , Inhibitory Concentration 50 , Ion Channels/chemistry , Male , Models, Chemical , Naproxen/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A series of amiloride derivatives modified at the 5-position of the pyrazine ring were evaluated as inhibitors of acid-sensing ion channel-3 (ASIC3), a novel target for the treatment of chronic pain.
Subject(s)
Amiloride/analogs & derivatives , Chemistry, Pharmaceutical/methods , Nerve Tissue Proteins/chemistry , Pain/drug therapy , Sodium Channels/chemistry , Acid Sensing Ion Channels , Acidosis , Amiloride/chemistry , Amines/chemistry , Animals , Drug Design , Electrophysiology , Inhibitory Concentration 50 , Male , Models, Chemical , Pyrazines/chemistry , Rats , Rats, Sprague-DawleyABSTRACT
A series of carbo- and heterocyclic alpha-hydroxy amide-derived bradykinin B1 antagonists was prepared and evaluated. A 4,4-difluorocyclohexyl alpha-hydroxy amide was incorporated along with a 2-methyl tetrazole in lieu of an oxadiazole to afford a suitable compound with good pharmacokinetic properties, CNS penetration, and clearance by multiple metabolic pathways.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Bradykinin B1 Receptor Antagonists , Tetrazoles/chemical synthesis , Tetrazoles/pharmacology , Amides/chemistry , Amides/pharmacokinetics , Animals , Central Nervous System/drug effects , Combinatorial Chemistry Techniques , Drug Design , Humans , Molecular Structure , Rats , Structure-Activity Relationship , Tetrazoles/chemistry , Tetrazoles/pharmacokineticsABSTRACT
After oral treatment (once daily) for 4 weeks with the potent bradykinin B(1) receptor antagonist methyl 3-chloro-3'-fluoro-4'-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)-amino]ethyl}-1,1'-biphenyl-2-carboxylate (MK-0686), rhesus monkeys (Macaca mulatta) exhibited significantly reduced systemic exposure of the compound in a dose-dependent manner, suggesting an occurrence of autoinduction of MK-0686 metabolism. This possibility is supported by two observations. 1) MK-0686 was primarily eliminated via biotransformation in rhesus monkeys, with oxidation on the chlorophenyl ring as one of the major metabolic pathways. This reaction led to appreciable formation of a dihydrodiol (M11) and a hydroxyl (M13) product in rhesus liver microsomes supplemented with NADPH. 2) The formation rate of these two metabolites determined in liver microsomes from MK-0686-treated groups was > or = 2-fold greater than the value for a control group. Studies with recombinant rhesus P450s and monoclonal antibodies against human P450 enzymes suggested that CYP2C75 played an important role in the formation of M11 and M13. The induction of this enzyme by MK-0686 was further confirmed by a concentration-dependent increase of its mRNA in rhesus hepatocytes, and, more convincingly, the enhanced CYP2C proteins and catalytic activities toward CYP2C75 probe substrates in liver microsomes from MK-0686-treated animals. Furthermore, a good correlation was observed between the rates of M11 and M13 formation and hydroxylase activities toward probe substrates determined in a panel of liver microsomal preparations from control and MK-0686-treated animals. Therefore, MK-0686, both a substrate and inducer for CYP2C75, caused autoinduction of its own metabolism in rhesus monkeys by increasing the expression of this enzyme.