ABSTRACT
Combinatorial optimization is a broadly attractive area for potential quantum advantage, but no quantum algorithm has yet made the leap. Noise in quantum hardware remains a challenge, and more sophisticated quantum-classical algorithms are required to bolster their performance. Here, we introduce an iterative quantum heuristic optimization algorithm to solve combinatorial optimization problems. The quantum algorithm reduces to a classical greedy algorithm in the presence of strong noise. We implement the quantum algorithm on a programmable superconducting quantum system using up to 72 qubits for solving paradigmatic Sherrington-Kirkpatrick Ising spin glass problems. We find the quantum algorithm systematically outperforms its classical greedy counterpart, signaling a quantum enhancement. Moreover, we observe an absolute performance comparable with a state-of-the-art semidefinite programming method. Classical simulations of the algorithm illustrate that a key challenge to reaching quantum advantage remains improving the quantum device characteristics.
ABSTRACT
The reliability and robustness of metabolite assignments in 1H NMR is complicated by numerous factors including variations in temperature, pH, buffer choice, ionic strength, and mixture composition that led to peak overlap and spectral crowding. As sample conditions fluctuate, peak drift and line broadening further complicate peak deconvolution and subsequent chemical assignment. We present a collection of 1D 1H NMR spectra of 54 common metabolites at varied pH (6.0 to 8.0 in 0.5 step increments) and temperature (290 K to 308 K) to quantify chemical shift variability to facilitate automated metabolite assignments. Our results illustrate the fundamental challenges with accurately assigning NMR peaks under varied environmental conditions prevalent in complex mixtures. Phosphorylated metabolites showed a larger variation in chemical shifts due to pH, whereas; amino acids showed a higher variation due to temperature. Mixtures of phosphorous compounds showed a consistently poor reliability in achieving an accurate assignment. Phosphorylated cholines, amino acids, and glycerols yielded a 40 % false negative rate for 7 out of 9 mixture conditions. Amino acids had a false negative rate of 57 % at 298 K and pH 8. Our results demonstrate that the automated assignments of complex biofluid mixtures require an expert to intervene to confirm the accuracy of metabolite assignments. Our analysis also indicates the need for reference databases to include spectra under a variety of conditions that includes mixtures and a range of pH and temperature to improve the accuracy and reproducibility of metabolite assignments.
Subject(s)
Amino Acids , Reproducibility of ResultsABSTRACT
NMR measurements of rotational and translational diffusion are used to characterize the solution behavior of a wide variety of therapeutic proteins and peptides. The timescales of motions sampled in these experiments reveal complicated intrinsic solution behavior such as flexibility, that is central to function, as well as self-interactions, stress-induced conformational changes and other critical attributes that can be discovery and development liabilities. Trends from proton transverse relaxation (R2 ) and hydrodynamic radius (Rh ) are correlated and used to identify and differentiate intermolecular from intramolecular interactions. In this study, peptide behavior is consistent with complicated multimer self-assembly, while multi-domain protein behavior is dominated by intramolecular interactions. These observations are supplemented by simulations that include effects from slow transient interactions and rapid internal motions. R2 -Rh correlations provide a means to profile protein motions as well as interactions. The approach is completely general and can be applied to therapeutic and target protein characterization.
Subject(s)
Nuclear Magnetic Resonance, Biomolecular , Peptides/chemistry , Proteins/chemistryABSTRACT
A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.
Subject(s)
Amides/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Pyrans/chemistry , Sulfonamides/chemistry , Animals , Binding Sites , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Dogs , Half-Life , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Molecular Docking Simulation , Protein Structure, Tertiary , Pyrans/chemical synthesis , Pyrans/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Heterocyclic Compounds, 2-Ring/pharmacology , Hypoglycemic Agents/pharmacology , Pyrans/pharmacology , Animals , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Dipeptidyl-Peptidase IV Inhibitors/toxicity , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Heterocyclic Compounds, 2-Ring/toxicity , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/toxicity , Pyrans/chemical synthesis , Pyrans/pharmacokinetics , Pyrans/toxicity , Structure-Activity RelationshipABSTRACT
A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the series provided inhibitors with good DPP-4 potency and selectivity over other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective, efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as a clinical candidate.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemical synthesis , Pyrans/chemical synthesis , Animals , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dogs , Enzyme Activation/drug effects , Glucose Tolerance Test , Haplorhini , Humans , Inhibitory Concentration 50 , Pyrans/chemistry , Pyrans/pharmacology , Rats , StereoisomerismABSTRACT
Diaryl-(4-piperidinyl)-pyrrole derivatives bearing cyclic amine substituents have been synthesized and evaluated as anticoccidial agents. Improvements in potency of Et-PKG inhibition, such as azetidine derivative 3a, and broad spectrum anticoccidial activities in feed, such as morpholine derivative 8c, have been achieved.
Subject(s)
Coccidiosis/drug therapy , Coccidiostats/pharmacology , Eimeria/drug effects , Pyrroles/pharmacology , Animals , Chickens , Coccidiostats/chemical synthesis , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Eimeria/enzymology , Female , Molecular Structure , Oocysts/drug effects , Oocysts/physiology , Protein Kinase Inhibitors/pharmacology , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
Diaryl imidazo[1,2-a]pyridine derivatives, such as 6a and 7i, have been synthesized and found to be potent inhibitors of parasite PKG activity. The most potent compounds are the 7-isopropylaminomethyl analog 6a and 2-isopropylamino analog 7i. These compounds are also fully active in in vivo assay as anticoccidial agents at 25 ppm in feed.
Subject(s)
Coccidiosis/drug therapy , Coccidiostats/pharmacology , Imidazoles/chemistry , Protein Kinase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Animals , Chemistry, Pharmaceutical/methods , Coccidiostats/chemistry , Cyclic GMP-Dependent Protein Kinases/metabolism , Drug Design , Eimeria tenella , Models, Chemical , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Molecular modeling was used to improve potency of the cyclohexylamine series. In addition, a 3-D QSAR method was used to gain insight for reducing off-target DPP-8/9 activities. Compounds 3, 4, and 5 were synthesized and found to be potent DPP-4 inhibitors, in particular 4 and 5 are designed to be highly selective against off-target DASH enzymes while maintaining potency on DPP-4.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Protease Inhibitors/pharmacology , Pyrimidines/pharmacology , Drug Design , Models, Molecular , Protease Inhibitors/chemistry , Pyrimidines/chemistry , Quantitative Structure-Activity RelationshipABSTRACT
Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we present the synthesis and biological activity of imidazo[1,2-a]pyridine anticoccidial agents. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.
Subject(s)
Coccidiostats/chemical synthesis , Coccidiostats/pharmacology , Eimeria/drug effects , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Biological Availability , Coccidiostats/chemistry , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Cyclic GMP-Dependent Protein Kinases/metabolism , Eimeria/physiology , Imidazoles/chemistry , Inhibitory Concentration 50 , Pyridines/chemistryABSTRACT
Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central beta-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC(50)=21 nM) with excellent in vivo activity and pharmacokinetic profile.
Subject(s)
Adenosine Deaminase Inhibitors , Cyclohexylamines/chemistry , Dipeptidyl-Peptidase IV Inhibitors , Glycoproteins/antagonists & inhibitors , HIV Protease Inhibitors/pharmacology , Pyrazines/pharmacology , Triazoles/pharmacology , Administration, Oral , Binding Sites , Crystallography, X-Ray , Dipeptidyl Peptidase 4 , Drug Design , HIV Protease Inhibitors/chemical synthesis , Humans , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Pyrazines/chemistry , Sitagliptin Phosphate , Triazoles/chemistryABSTRACT
Following the discovery of N-acyl-1,4-diazepan-2-one as a novel pharmacophore for potent and selective DPP-4 inhibitors, optimization of this new lead with different substitution on the seven-membered ring resulted in several highly potent and selective, orally bioavailable, and efficacious DPP-4 inhibitors, such as 3R-methyl-1-cyclopropyl-1,4-diazepan-2-one derivative 9i (DPP-4 IC(50)=8.0 nM) and 3R,6R-dimethyl-1,4-diazepan-2-one derivative 14a (DPP-4 IC(50)=9.7 nM).
Subject(s)
Azepines/chemical synthesis , Chemistry, Pharmaceutical/methods , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Administration, Oral , Animals , Azepines/pharmacology , Drug Design , Inhibitory Concentration 50 , Male , Mice , Models, Chemical , Molecular Conformation , Rats , Rats, Sprague-DawleyABSTRACT
Replacement of the triazolopiperazine ring of sitagliptin (DPP-4 IC(50)=18nM) with 3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one gave dipeptidyl peptidase IV (DPP-4) inhibitor 1 which is potent (DPP-4 IC(50)=2.6nM), selective, and efficacious in an oral glucose tolerance test in mice. It was selected for extensive preclinical development as a potential back-up candidate to sitagliptin.
Subject(s)
Azepines/chemistry , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors , Hypoglycemic Agents/chemistry , Protease Inhibitors/chemistry , Animals , Azepines/therapeutic use , Crystallography, X-Ray , Dipeptidyl Peptidase 4/chemistry , Hypoglycemic Agents/therapeutic use , Protease Inhibitors/therapeutic use , Protein Conformation , Pyrazines/chemistry , Pyrazines/therapeutic use , Rats , Rats, Inbred Strains , Sitagliptin Phosphate , Triazoles/chemistry , Triazoles/therapeutic useABSTRACT
Compounds 10a-10d and 10i are very potent inhibitors of Eimeria tenella cGMP-dependent protein kinase (0.081-0.32 nM) and are very efficacious antiparasitic agents in vivo when administered to chickens at 12.5-25 ppm levels in the feed.
Subject(s)
Coccidiostats/chemical synthesis , Coccidiostats/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Pyridines/chemistry , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Coccidiostats/chemistry , Eimeria/drug effects , Imidazoles/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
2-(4-Fluorophenyl)-3-(4-pyridinyl)-5-substituted pyrroles were prepared and evaluated as anticoccidial agents in both in vitro and in vivo assays. Among the compounds evaluated, the dimethylamine-substituted pyrrole 19a is the most potent inhibitor of Eimeria tenella PKG (cGMP-dependent protein kinase). Further SAR studies on the side chain of the 2-pyrrolidine nitrogen did not enhance in vivo anticoccidial activity.
Subject(s)
Coccidiostats/chemical synthesis , Coccidiostats/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Animals , Coccidiostats/chemistry , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Eimeria tenella/drug effects , Eimeria tenella/enzymology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
Compounds 10a (IC50 110 pM) and 21 (IC50 40 pM) are the most potent inhibitors of Eimeria tenella cGMP-dependent protein kinase activity reported to date and are efficacious in the in vivo antiparasitic assay when administered to chickens at 12.5 and 6.25 ppm levels in the feed. However, both compounds are positive in the Ames microbial mutagenesis assay which precludes them from further development as antiprotozoal agents in the absence of negative lifetime rodent carcinogenicity studies.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Eimeria tenella/drug effects , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Pyridines/chemical synthesis , Animal Feed , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Chickens , Coccidiosis/drug therapy , Eimeria tenella/enzymology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Male , Molecular Structure , Mutagenicity Tests , Oocysts/drug effects , Parasitic Sensitivity Tests , Pyridines/chemistry , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Diaryl-(4-piperidinyl)-pyrrole derivatives bearing hydroxylated N-alkyl substituents have been synthesized and evaluated as anticoccidial agents. High potency in Et-PKG inhibition and broad-spectrum anticoccidial activities have been observed on compounds, such as 4b and 5h, which are fully efficacious in vivo at 50 ppm in feed.
Subject(s)
Coccidiostats/chemistry , Coccidiostats/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Hydroxylation , Structure-Activity RelationshipABSTRACT
Several analogs of 2,3-diaryl pyrroles were synthesized and evaluated as inhibitors of Eimeria tenella cGMP-dependent protein kinase and in in vivo anticoccidial assays. A 4-fluorophenyl group enhances both in vitro and in vivo activities. The most potent analogs are the 5-(N-methyl, N-ethyl, and N-methylazetidine methyl) piperidyl derivatives 12, 23, and 34. These compounds have a broad spectrum of activity. Based on the in vivo efficacy and cost of synthesis, the N-ethyl analog 23 was chosen as a novel anticoccidial agent for a field trial.
