ABSTRACT
ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to a phase I clinical trial for the treatment of multiple myeloma. Due to its large size and structural complexity, ABBV-467 is a challenging synthetic target. Herein, we describe the synthesis of ABBV-467 on a decagram scale, which enabled preclinical characterization. The strategy is convergent and stereoselective, featuring a hindered biaryl cross coupling, enantioselective hydrogenation, and conformationally preorganized macrocyclization by C-O bond formation as key steps.
Subject(s)
Antineoplastic Agents , Myeloid Cell Leukemia Sequence 1 Protein , Antineoplastic Agents/pharmacology , Hydrogenation , Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitorsABSTRACT
Cyclin-dependent kinase 9 (CDK9) is a serine/threonine kinase involved in the regulation of transcription elongation. An inhibition of CDK9 downregulates a number of short-lived proteins responsible for tumor maintenance and survival, including the antiapoptotic BCL-2 family member MCL-1. As pan-CDK inhibitors under development have faced dosing and toxicity challenges in the clinical setting, we generated selective CDK9 inhibitors that could be amenable to an oral administration. Here, we report the lead optimization of a series of azaindole-based inhibitors. To overcome early challenges with promiscuity and cardiovascular toxicity, carboxylates were introduced into the pharmacophore en route to compounds such as 14 and 16. These CDK9 inhibitors demonstrated a reduced toxicity, adequate pharmacokinetic properties, and a robust in vivo efficacy in mice upon oral dosing.
ABSTRACT
Aberrant gene activation driven by the histone acetyltransferases p300 and CREB binding protein (CBP) has been linked to several diseases, including cancers. Because of this, many efforts have been aimed toward the targeting of the closely related paralogues, p300 and CBP, but these endeavors have been exclusively directed toward noncovalent inhibitors. X-ray crystallography of A-485 revealed that both p300 and CBP possess a cysteine (C1450) near the active site, thus rendering covalent inhibition an attractive chemical approach. Herein we report the development of compound 2, an acrylamide-based inhibitor of p300/CBP that forms a covalent adduct with C1450. We demonstrated using mass spectrometry that compound 2 selectively targets C1450, and we also validated covalent binding using kinetics experiments and cellular washout studies. The discovery of covalent inhibitor 2 gives us a unique tool for the study of p300/CBP biology.
ABSTRACT
In continuation of our previous research towards the discovery of potent, selective and drug-like Wee1 inhibitors, 2 novel series of biaryl heterocycles were designed, synthesized and evaluated. The new biaryl cores were designed to enable structure-activity exploration of substituents at C-8 or N-8 which were used for tuning compound properties and to improve compound profiles. The lead molecule 33 demonstrated a desirable pharmacokinetic profile and potentiated the anti-proliferative activity of irinotecan in vivo when dosed orally in the human breast MX-1 xenograft model.
Subject(s)
Cell Cycle Proteins/metabolism , Heterocyclic Compounds/metabolism , Protein-Tyrosine Kinases/metabolism , Humans , Structure-Activity RelationshipABSTRACT
We have investigated the SAR of a series of pyrimidinone-containing Cdc7 kinase inhibitors. A wide range of amine substitutions give potent compounds with activities (K(i)) less than 1nM. Kinase selectivity is reasonable and cytotoxicity corresponds to inhibition of MCM2 phosphorylation.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Amines/chemistry , Amines/pharmacology , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Humans , Minichromosome Maintenance Complex Component 2 , Nuclear Proteins/metabolism , Phosphorylation/drug effects , Protein Serine-Threonine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment of type 2 diabetes. They exert their beneficial effects by increasing the levels of active glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are two important incretins for glucose homeostasis. Starting from a high-throughput screening hit, we were able to identify a series of piperidinone- and piperidine-constrained phenethylamines as novel DPP4 inhibitors. Optimized compounds are potent, selective, and have good pharmacokinetic profiles.
Subject(s)
Adenosine Deaminase Inhibitors , Dipeptidyl-Peptidase IV Inhibitors , Glycoproteins/antagonists & inhibitors , Phenethylamines/chemical synthesis , Piperidines/chemical synthesis , Animals , Biological Availability , Crystallography, X-Ray , Dipeptidyl Peptidase 4 , Humans , Molecular Conformation , Phenethylamines/pharmacokinetics , Phenethylamines/pharmacology , Piperidines/pharmacokinetics , Piperidines/pharmacology , Piperidones/chemical synthesis , Piperidones/pharmacokinetics , Piperidones/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.
Subject(s)
Chemistry, Pharmaceutical/methods , Dipeptidyl-Peptidase IV Inhibitors , Enzyme Inhibitors/chemical synthesis , Phenethylamines/chemical synthesis , Pyrrolidines/chemical synthesis , Animals , Blood Glucose/metabolism , Cyclohexenes/chemistry , Diabetes Mellitus, Type 2/drug therapy , Drug Design , Enzyme Inhibitors/chemistry , Female , Hypoglycemic Agents/pharmacology , Models, Chemical , Molecular Conformation , Phenethylamines/chemistry , Pyrrolidines/chemistry , RatsABSTRACT
A series of novel benzoxazole benzenesulfonamides was synthesized as inhibitors of fructose-1,6-bisphosphatase (FBPase-1). Extensive SAR studies led to a potent inhibitor, 53, with an IC(50) of 0.57microM. Compound 17 exhibited excellent bioavailability and a good pharmacokinetic profile in rats.
Subject(s)
Enzyme Inhibitors/pharmacology , Fructose-Bisphosphatase/antagonists & inhibitors , Sulfonamides/pharmacology , Allosteric Regulation , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Models, Molecular , Rats , Sulfonamides/chemistry , Sulfonamides/pharmacokineticsABSTRACT
We have identified benzoxazole benzenesulfonamide 1 as a novel allosteric inhibitor of fructose-1,6-bisphosphatase (FBPase-1). X-ray crystallographic and biological studies of 1 indicate a distinct binding mode that recapitulates features of several previously reported FBPase-1 inhibitor classes.
Subject(s)
Benzoxazoles/chemistry , Enzyme Inhibitors/pharmacology , Fructose-Bisphosphatase/antagonists & inhibitors , Sulfonamides/pharmacology , Allosteric Regulation , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Fructose-Bisphosphatase/metabolism , Models, Molecular , Protein Binding , Sulfonamides/chemistry , Sulfonamides/metabolismABSTRACT
The asymmetric allenylboration of representative aldehydes with the stable, storable 1 is reported. Easily and efficiently prepared in either enantiomeric form from the air-stable crystalline 4 through simple Grignard procedures, 1 gives 6 cleanly. The latter is easily isolated in high yield and ee with predictable stereochemistry. The procedure also regenerates 4 for its direct conversion back to 1 and facilitates the efficient recovery of the pseudoephedrine. The net process is the synthetic equivalent of the asymmetric addition of allenylmagnesium bromide to aldehydes. [reaction: see text]
Subject(s)
Alcohols/chemical synthesis , Aldehydes/chemistry , Alkanes/chemistry , Boranes/chemistry , Boranes/chemical synthesis , Catalysis , Ephedrine/chemical synthesis , Indicators and ReagentsABSTRACT
Hepatic blockade of glucocorticoid receptors (GR) suppresses glucose production and thus decreases circulating glucose levels, but systemic glucocorticoid antagonism can produce adrenal insufficiency and other undesirable side effects. These hepatic and systemic responses might be dissected, leading to liver-selective pharmacology, when a GR antagonist is linked to a bile acid in an appropriate manner. Bile acid conjugation can be accomplished with a minimal loss of binding affinity for GR. The resultant conjugates remain potent in cell-based functional assays. A novel in vivo assay has been developed to simultaneously evaluate both hepatic and systemic GR blockade; this assay has been used to optimize the nature and site of the linker functionality, as well as the choice of the GR antagonist and the bile acid. This optimization led to the identification of A-348441, which reduces glucose levels and improves lipid profiles in an animal model of diabetes.
Subject(s)
Bridged-Ring Compounds/chemical synthesis , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/chemical synthesis , Liver/metabolism , Receptors, Glucocorticoid/antagonists & inhibitors , Animals , Bile Acids and Salts/chemistry , Binding Sites , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , CHO Cells , Cells, Cultured , Computer Simulation , Cricetinae , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Type 2/blood , Glucose/biosynthesis , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/physiology , Male , Mice , Models, Molecular , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/physiology , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis, activity, metabolic stability, and pharmacokinetics of steroidal and nonsteroidal glucocorticoid receptor modulator-statin hybrids is reported. Potent steroidal antagonist-statin hybrids like 22 (h-GR binding IC(50)=7 nM) and nonsteroidal modulator hybrids like 16 (h-GR binding IC(50)=2 nM) were discovered. Appending a 'statin'-like diol-acid group to the modulators dramatically improved metabolic stability (and in some cases hepatocyte activity), but did not impart hepatoselectivity.