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
Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cytokines/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors , Urea/analogs & derivatives , Urea/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Cytokines/chemistry , Cytokines/metabolism , Drug Discovery , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Humans , Isoindoles/chemistry , Isoindoles/pharmacokinetics , Isoindoles/pharmacology , Isoindoles/therapeutic use , Mice , Models, Molecular , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Nicotinamide Phosphoribosyltransferase/chemistry , Nicotinamide Phosphoribosyltransferase/metabolism , Structure-Activity Relationship , Urea/pharmacokinetics , Urea/therapeutic useABSTRACT
Cancer cells are highly reliant on NAD+-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ salvage from nicotinamide, has been investigated as a target for anticancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM-competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD+, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD+ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo antitumor efficacy. Mol Cancer Ther; 16(7); 1236-45. ©2017 AACR.
Subject(s)
Colorectal Neoplasms/drug therapy , Cytokines/antagonists & inhibitors , Enzyme Inhibitors/administration & dosage , Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors , Adenosine Triphosphate/genetics , Adenosine Triphosphate/metabolism , Animals , Calcium Signaling/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Cytokines/genetics , DNA Repair/drug effects , Enzyme Activation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , HCT116 Cells , Humans , Mice , NAD/metabolism , Nicotinamide Phosphoribosyltransferase/genetics , Xenograft Model Antitumor AssaysABSTRACT
The design and enzyme activities of a novel class of imidazo[2,1-b]thiazoles is presented.
Subject(s)
ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Thiazoles/pharmacology , Models, Molecular , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/analogs & derivatives , Adamantane/chemical synthesis , Piperazines/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , Adamantane/pharmacokinetics , Animals , Cell Line , Humans , In Vitro Techniques , Mice , Microsomes, Liver/metabolism , Piperazines/pharmacokinetics , Rats , Stereoisomerism , Structure-Activity Relationship , Tissue DistributionABSTRACT
The optimization of a series of nonsteroidal glucocorticoid modulators is reported. Potent selective GR ligands that have improved metabolic stability were discovered typified by the subnanomolar acid 12 (GR binding IC(50)=0.6 nM).
Subject(s)
Receptors, Glucocorticoid/drug effects , Humans , Ligands , Protein Binding , Receptors, Glucocorticoid/metabolismABSTRACT
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.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Receptors, Glucocorticoid/drug effects , Half-Life , Hepatocytes/drug effects , Hepatocytes/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Glucocorticoid/chemistryABSTRACT
Bile acid conjugates of a selective nonsteroidal glucocorticoid receptor modulator were prepared and evaluated. Potent GR binding conjugates that showed improved metabolic stability were discovered. However, cellular potency and pharmacokinetics were not substantially improved.
Subject(s)
Bile Acids and Salts/chemistry , Receptors, Glucocorticoid/drug effects , Animals , Bile Acids and Salts/pharmacokinetics , Biological Availability , Rats , Rats, Sprague-DawleyABSTRACT
Biaryl amides derived from a reported series of ureas 1 were evaluated and found to be potent human glucagon receptor antagonists. The benzofuran analogue 6i was administered in Sprague-Dawley rats and blocked the effects of an exogenous glucagon challenge.
Subject(s)
Amides/pharmacology , Receptors, Glucagon/antagonists & inhibitors , Amides/chemistry , Animals , Haplorhini , Humans , Mice , Rats , Rats, Sprague-DawleyABSTRACT
A new class of selective nonsteroidal glucocorticoid receptor modulators typified by N-[3-[benzyl-(4-chloro-2-fluoro-benzyl)-amino]-2-methyl-phenyl]-methanesulfonamide 19 has been discovered.
Subject(s)
Receptors, Glucocorticoid/drug effects , Animals , Benzyl Compounds , Humans , Rats , Structure-Activity Relationship , SulfonamidesABSTRACT
A beta-C-glucuronide conjugate of the glucocorticoid receptor antagonist, Mifepristone 1, was prepared which maintained binding affinity, had modest in vitro activity, and was metabolically more stable than the parent. Pharmacokinetic studies suggest that the conjugate is recognized by the liver like O-glucuronides and may undergo a portion of the enterohepatic recirculation loop.
