ABSTRACT
In recent years, the first generation of ß-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug-drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/chemistry , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/chemistry , Cytochrome P-450 CYP2D6/chemistry , Drug Interactions , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Amino Acid Sequence , Amyloidogenic Proteins/metabolism , Animals , Crystallography, X-Ray , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/metabolism , Drug Design , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Inhibitory Concentration 50 , Male , Mice, Inbred Strains , Models, Molecular , Molecular Sequence Data , Protease Inhibitors/administration & dosage , Protease Inhibitors/pharmacokinetics , Pyrazoles/chemistry , Structure-Activity RelationshipABSTRACT
New drugs introduced to the market every year represent a privileged structure for a particular biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of twenty-six NCEs that were launched or approved worldwide in 2012 and two additional drugs which were launched at the end of 2011.
Subject(s)
Pharmaceutical Preparations/chemical synthesis , Molecular Structure , Pharmaceutical Preparations/chemistryABSTRACT
Herein we describe the design and synthesis of a novel series of γ-secretase modulators (GSMs) that incorporates a pyridopiperazine-1,6-dione ring system. To align improved potency with favorable ADME and in vitro safety, we applied prospective physicochemical property-driven design coupled with parallel medicinal chemistry techniques to arrive at a novel series containing a conformationally restricted core. Lead compound 51 exhibited good in vitro potency and ADME, which translated into a favorable in vivo pharmacokinetic profile. Furthermore, robust reduction of brain Aß42 was observed in guinea pig at 30 mg/kg dosed orally. Through chemical biology efforts involving the design and synthesis of a clickable photoreactive probe, we demonstrated specific labeling of the presenilin N-terminal fragment (PS1-NTF) within the γ-secretase complex, thus gaining insight into the binding site of this series of GSMs.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Pyridazines/chemical synthesis , Pyridines/chemical synthesis , Amyloid Precursor Protein Secretases/chemistry , Amyloid beta-Peptides/metabolism , Animals , Binding Sites , CHO Cells , Cricetinae , Cricetulus , Drug Design , Guinea Pigs , HEK293 Cells , Humans , Peptide Fragments/metabolism , Presenilin-1/chemistry , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Pyridines/pharmacokinetics , Pyridines/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
New drugs are introduced to the market every year and each represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of 26 NCEs that were launched in the world in 2011.
Subject(s)
Drug Approval , Drug Design , Pharmaceutical Preparations/chemical synthesis , HumansABSTRACT
A stereoselective synthesis of spiropiperidine compounds, exemplified by compound 1, was developed, which was based upon the late stage N-arylation of a 1,8-diazaspiro[4.5]dec-3-en-2-one pharmacophore. Previously, compound 1 was prepared in low overall yield from piperidinone 2 via the Strecker reaction. A new route was developed, which employed the stereospecific Corey-Link reaction of an enantiomerically pure trichloromethylcarbinol to give a template compound amenable to late stage N-arylation.
Subject(s)
Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/chemistry , Aza Compounds/chemical synthesis , Methanol/chemistry , Piperidines/chemical synthesis , Spiro Compounds/chemical synthesis , Aza Compounds/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Piperidines/chemistry , Protease Inhibitors , Spiro Compounds/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We report the discovery and optimization of a novel series of dihydrobenzofuran amides as γ-secretase modulators (GSMs). Strategies for aligning in vitro potency with drug-like physicochemical properties and good microsomal stability while avoiding P-gp mediated efflux are discussed. Lead compounds such as 35 and 43 have moderate to good in vitro potency and excellent selectivity against Notch. Good oral bioavailability was achieved as well as robust brain Aß42 lowering activity at 100 mg/kg po dose.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Drug Design , Administration, Oral , Amides/chemistry , Animals , Benzofurans/chemical synthesis , Benzofurans/chemistry , Benzofurans/pharmacology , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Guinea Pigs , Inhibitory Concentration 50 , Molecular Structure , Protein Binding , RatsABSTRACT
New drugs are introduced to the market every year and each represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of 15 NCEs that were launched anywhere in the world in 2010.
Subject(s)
Chemistry Techniques, Synthetic/methods , Drug Design , Pharmaceutical Preparations/chemical synthesis , Molecular Structure , Pharmaceutical Preparations/chemistryABSTRACT
The synthesis and structure-activity relationships for a novel series of 6-amino-4-(pyrimidin-4-yl)pyridones derived from a high throughput screening hit are discussed. Optimization of lead matter afforded compounds with good potency, selectivity and central nervous system (CNS) exposure.
Subject(s)
Glycogen Synthase Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyridones/chemical synthesis , Central Nervous System/drug effects , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Pyridones/chemistry , Pyridones/pharmacology , Structure-Activity RelationshipABSTRACT
New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the syntheses of 21 NCEs marketed in 2009.
Subject(s)
Drug Approval , Drug Design , Molecular Targeted Therapy , Pharmaceutical Preparations/chemical synthesis , HumansABSTRACT
3-Hydroxyquinolin-2(1H)-one (2) was discovered by high throughput screening in a functional assay to be a potent inhibitor of human DAAO, and its binding affinity was confirmed in a Biacore assay. Cocrystallization of 2 with the human DAAO enzyme defined the binding site and guided the design of new analogues. The SAR, pharmacokinetics, brain exposure, and effects on cerebellum D-serine are described. Subsequent evaluation against the rat DAAO enzyme revealed a divergent SAR versus the human enzyme and may explain the high exposures of drug necessary to achieve significant changes in rat or mouse cerebellum D-serine.
Subject(s)
D-Amino-Acid Oxidase/antagonists & inhibitors , Hydroxyquinolines/pharmacology , Hydroxyquinolines/pharmacokinetics , Animals , Cerebellum/metabolism , Crystallography, X-Ray , Drug Discovery , Drug Evaluation, Preclinical , Humans , Hydroxyquinolines/chemical synthesis , Male , Mice , Rats , Rats, Sprague-Dawley , Serine/metabolism , Structure-Activity RelationshipABSTRACT
New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the syntheses of 18 NCEs marketed in 2008.
Subject(s)
Pharmaceutical Preparations/chemical synthesis , Drug Approval , Humans , Molecular Conformation , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/classificationABSTRACT
New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the syntheses of 19 NCEs marketed in 2007.
Subject(s)
Drug Design , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/chemical synthesis , Humans , Molecular Structure , Stereoisomerism , Time FactorsABSTRACT
Structure-activity relationship (SAR) studies of novel 5-alkyl and 5-aryl/heteroaryl substituted 1,2,4-triazoles are described. The in vitro activity is compared to the pyrazole class of compounds with analogous side chains to delineate the contribution of the triazole ring nitrogen in binding to the active site. Both series are quite potent and selective in the canine whole blood (CWB) COX-2 assay, suggesting the increased binding contribution of the hydrophobic side chains.
Subject(s)
Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/metabolism , Ethers/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Sulfhydryl Compounds/chemical synthesis , Sulfhydryl Compounds/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacology , Alkylation , Animals , Cyclooxygenase 2 Inhibitors/blood , Cyclooxygenase 2 Inhibitors/chemistry , Dogs , Inhibitory Concentration 50 , Molecular Structure , Pyrazoles/blood , Pyrazoles/chemistry , Structure-Activity Relationship , Sulfhydryl Compounds/blood , Sulfhydryl Compounds/chemistry , Triazoles/blood , Triazoles/chemistryABSTRACT
New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. To these ends, this review covers the syntheses of 22 NCEs marketed in 2005.
Subject(s)
Drug Design , Pharmaceutical Preparations/classification , Molecular StructureABSTRACT
The structure-activity relationship toward canine COX-1 and COX-2 in vitro whole blood activity of 4-hydrogen versus 4-cyano substituted 5-aryl or 5-heteroatom substituted N-phenyl versus N-2-pyridyl sulfone pyrazoles is discussed. The differences between the pairs of compounds with the 4-nitrile pyrazole derivatives having substantially improved in vitro activity are highlighted for both COX-2 and COX-1. This difference in activity may be due to the contribution of the hydrogen bond of the 4-cyano group with Ser 530 as shown by our molecular modeling studies. In addition, our model suggests a potential contribution from hydrogen bonding of the pyridyl nitrogen to Tyr 355 for the increased activity over the phenyl sulfone analogs.
Subject(s)
Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/pharmacology , Nitriles/chemistry , Nitriles/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Sulfones/chemistry , Sulfones/pharmacology , Animals , Binding Sites/drug effects , Celecoxib , Cyclooxygenase 1/metabolism , Dogs , Drug Design , Humans , Hydrogen Bonding , In Vitro Techniques , Indicators and Reagents , Kinetics , Models, Molecular , Structure-Activity Relationship , Sulfonamides/pharmacologyABSTRACT
New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. To these ends, this review covers the syntheses of 16 NCEs marketed in 2006.
Subject(s)
Pharmaceutical Preparations/chemical synthesis , Pharmaceutical Preparations/classificationABSTRACT
The discovery of heteroaryl-phenyl-substituted pyrazole derivatives as canine selective COX-2 inhibitors is described. Structure-activity relationship (SAR) studies of this class of compounds led to the identification of compound 1 which demonstrated a canine whole blood COX-2 inhibitory IC50 of 12 nM and selectivity ratio of COX-1/COX-2 greater than 4000-fold.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemical synthesis , Pyrazoles/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/pharmacology , Dogs , Inhibitory Concentration 50 , Pyrazoles/pharmacology , Structure-Activity RelationshipABSTRACT
Structure-activity relationship (SAR) studies of novel 2-[3-trifluoromethyl-5-alkyl(thio)ether pyrazo-1-yl]-5-methanesulfonyl pyridine derivatives for canine COX enzymes are described. The 4-cyano-5-alkyl ethers were found to have excellent potency and selectivity, whereas the 5-thioethers were potent but less selective than the ether analogs in a canine whole blood (CWB) COX-2 assay.
Subject(s)
Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/metabolism , Ethers/chemistry , Pyrazoles/chemistry , Sulfhydryl Compounds/chemistry , Alkylation , Animals , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacokinetics , Dogs , Inhibitory Concentration 50 , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of conformationally constrained bicyclic derivatives derived from SR141716 was prepared and evaluated as hCB(1)-R antagonists and inverse agonists. Optimization of the structure-activity relationships around the 2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one derivative 2a led to the identification of two compounds with oral activity in rodent feeding models (2h and 4a). Replacement of the PP group in 2h with other bicyclic groups resulted in a loss of binding affinity.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Feeding Behavior/drug effects , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Animals , Binding Sites , Feeding Behavior/physiology , Models, Biological , Piperidines/chemistry , Pyrazoles/chemistry , Pyrazolones/chemistry , Pyrimidinones/chemistry , Receptor, Cannabinoid, CB1/agonists , Rimonabant , Rodentia , Structure-Activity RelationshipABSTRACT
Structure-activity relationship (SAR) studies of the novel 2-[3-di and trifluoromethyl-5-alkylamino pyrazo-1-yl]-5-methanesulfonyl (SO(2)Me)/sulfamoyl (SO(2)NH(2))-pyridine derivatives for canine COX enzymes are described. The studies led to the identification of 2e as lead with potent in vitro activity, selectivity, and in vivo activity in dogs and cats.
