ABSTRACT
Selective inhibitors of phosphoinositide 3-kinase delta are of interest for the treatment of inflammatory diseases. Initial optimization of a 3-substituted indazole hit compound targeting the kinase PIM1 focused on improving selectivity over GSK3ß through consideration of differences in the ATP binding pockets. Continued kinase cross-screening showed PI3Kδ activity in a series of 4,6-disubstituted indazole compounds, and subsequent structure-activity relationship exploration led to the discovery of an indole-containing lead compound as a potent PI3Kδ inhibitor with selectivity over the other PI3K isoforms.
ABSTRACT
A palladium(0)-catalyzed rearrangement of piperidones and piperidines bearing a spirocyclopropane ring was developed. The ring expansion reaction led to a variety of functionalized caprolactam and azepane products in good to excellent yields. Experimental and computational mechanistic studies revealed an initial oxidative addition of the distal carbon-carbon bond of a cyclopropane ring to the palladium(0) catalyst and the relief of ring strain as a driving force for product formation.
ABSTRACT
The identification of a new series of RORc inverse agonists is described. Comprehensive structure-activity relationship studies of this reversed sulfonamide series identified potent RORc inverse agonists in biochemical and cellular assays which were also selective against a panel of nuclear receptors. Our work has contributed a compound that may serve as a useful in vitro tool to delineate the complex biological pathways involved in signalling through RORc. An X-ray co-crystal structure of an analogue with RORc has also provided useful insights into the binding interactions of the new series.
Subject(s)
Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Sulfonamides/chemistry , Binding Sites , Cell Survival/drug effects , Crystallography, X-Ray , Cytokines/biosynthesis , Drug Inverse Agonism , HEK293 Cells , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Molecular Dynamics Simulation , Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Protein Binding , Protein Structure, Tertiary , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/toxicityABSTRACT
Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.
Subject(s)
Antirheumatic Agents/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Imidazoles/chemical synthesis , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Pyridines/chemical synthesis , Pyrroles/chemical synthesis , Administration, Oral , Animals , Antirheumatic Agents/chemistry , Antirheumatic Agents/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Experimental/etiology , Biological Availability , Cell Membrane Permeability , Collagen , Crystallography, X-Ray , Dogs , Haplorhini , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Janus Kinase 1/chemistry , Janus Kinase 2/chemistry , Madin Darby Canine Kidney Cells , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Pyridines/chemistry , Pyridines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Rats , StereoisomerismABSTRACT
A new series of potent TG2 inhibitors are reported that employ a 4-aminopiperidine core bearing an acrylamide warhead. We establish the structure-activity relationship of this new series and report on the transglutaminase selectivity and in vitro ADME properties of selected compounds. We demonstrate that the compounds do not conjugate glutathione in an in vitro setting and have superior plasma stability over our previous series.
ABSTRACT
The SAR around a V1b antagonist HTS hit 3 was explored to produce a series of thiazole sulfonamides as a lead series with selectivity over the related V1 and oxytocin receptors.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Sulfonamides/chemistry , Animals , High-Throughput Screening Assays , Rats , Receptors, Oxytocin/antagonists & inhibitors , Receptors, Oxytocin/metabolism , Receptors, Vasopressin/metabolism , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
A series of sulfonamide CCR2 antagonists was identified by high-throughput screening. Management of molecular weight and physical properties, in particular moderation of lipophilicity and study of pK(a), yielded highly potent CCR2 antagonists exhibiting good pharmacokinetic properties and improved potency in the presence of human plasma.
Subject(s)
Receptors, CCR2/antagonists & inhibitors , Sulfonamides/pharmacology , Animals , Dose-Response Relationship, Drug , High-Throughput Screening Assays , Humans , Mice , Molecular Structure , Receptors, CCR1/antagonists & inhibitors , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
A new class of selective MMP-12 inhibitors have been identified via high throughput screening. Crystallization with MMP-12 confirmed the mode of binding and allowed initial optimization to be carried out using classical structure based design.
Subject(s)
Carboxylic Acids/chemistry , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemistry , Animals , Binding Sites , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Crystallography, X-Ray , Drug Design , Guinea Pigs , Humans , Matrix Metalloproteinase 12/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported.
Subject(s)
Imidazolidines/chemistry , Positron-Emission Tomography , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Cats , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Imidazolidines/chemical synthesis , Imidazolidines/pharmacology , Ligands , Receptors, Dopamine D3/metabolism , Structure-Activity RelationshipABSTRACT
A series of new Ru(II) complex salts trans-[Ru(NH(3))(4)(L(1))(L(2))](PF(6))(n) [n = 2, L(1) = 4-acetylpyridine (4-acpy) and L(2) = 4-(dimethylamino)pyridine (dmap) (1), 4-(dimethylamino)benzonitrile (dmabn) (2), 4-picoline (4-pic) (3), or 1-methylimidazole (1-MeIm) (4); n = 3, L(1) = N-methyl-4,4'-bipyridinium (MeQ(+)) and L(2) = dmap (6), dmabn (7), 1-MeIm (8), 4-acpy (9), or phenothiazine (PTZ) (10); n = 2, L(1) = dmap and L(2) = 4-pyridinecarboxaldehyde (pyca) (12) or ethyl isonicotinate (isne) (13)] have been synthesized and fully characterized. These complexes display intense, visible metal-to-ligand charge-transfer (MLCT) absorptions which are highly solvatochromic. An X-ray crystal structure determination has been carried out for trans-[Ru(NH(3))(4)(MeQ(+))(PTZ)](PF(6))(3).Me(2)CO (10.Me(2)CO). This salt, empirical formula C(26)H(38)F(18)N(7)OP(3)RuS, crystallizes in the hexagonal system, space group P6(3), with a = b = 17.853(4) Å, c = 21.514(6) Å, and Z = 6. The MeQ(+) ligand adopts an almost planar conformation, with a torsion angle of 9.6 degrees between the two pyridyl rings. The dipolar cations exhibit a strong projected component along the z axis, but crystal twinning precludes second-harmonic generation. Measurements of the first hyperpolarizability beta by using the hyper-Rayleigh scattering technique at 1064 nm yield very large values in the range (232-621) x 10(-30) esu, the largest being for trans-[Ru(NH(3))(4)(MeQ(+))(dmabn)](PF(6))(3) (7). These beta values are resonance enhanced via the MLCT excitations. A correlation between beta and the MLCT absorption energy confirms that this excitation is the primary contributor to beta. The two-level model yields static hyperpolarizabilities beta(0) in the range (10-130) x 10(-30) esu, with trans-[Ru(NH(3))(4)(MeQ(+))(dmap)](PF(6))(3) (6) having the largest. The beta(0) values of the complexes of the bipyridyl ligand MeQ(+) are larger than those of their analogues containing monopyridyl ligands because of extended conjugation. beta(0) correlates with the MLCT energy only when the MLCT absorption is sufficiently far from the second harmonic at 532 nm.
