ABSTRACT
We initiated our structure-activity relationship (SAR) studies for novel ACC1 inhibitors from 1a as a lead compound. Our initial SAR studies of 1H-Pyrrolo[3,2-b]pyridine-3-carboxamide scaffold revealed the participation of HBD and HBA for ACC1 inhibitory potency and identified 1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative 1c as a potent ACC1 inhibitor. Although compound 1c had physicochemical and pharmacokinetic (PK) issues, we investigated the 1H-pyrrolo[3,2-b]pyridine core scaffold to address these issues. Accordingly, this led us to discover a novel 1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative 1k as a promising ACC1 inhibitor, which showed potent ACC1 inhibition as well as sufficient cellular potency. Since compound 1k displayed favorable bioavailability in mouse cassette dosing PK study, we conducted in vivo Pharmacodynamics (PD) studies of this compound. Oral administration of 1k significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at a dose of 100â¯mg/kg. Accordingly, our novel series of potent ACC1 inhibitors represent useful orally-available research tools, as well as potential therapeutic agents for cancer and fatty acid related diseases.
Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Amides/chemistry , Drug Design , Enzyme Inhibitors/chemical synthesis , Pyridines/chemistry , Acetyl-CoA Carboxylase/metabolism , Administration, Oral , Amides/metabolism , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , HCT116 Cells , Humans , Male , Malonyl Coenzyme A/metabolism , Mice , Mice, Inbred ICR , Neoplasms/drug therapy , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
We initiated our structure-activity relationship (SAR) studies for selective ACC1 inhibitors from 1a as a lead compound. SAR studies of bicyclic scaffolds revealed many potent and selective ACC1 inhibitors represented by 1f; however most of them had physicochemical issues, particularly low aqueous solubility and potent CYP inhibition. To address these two issues and improve the druglikeness of this chemical series, we converted the bicyclic scaffold into a monocyclic framework. Ultimately, this lead us to discover a novel monocyclic derivative 1q as a selective ACC1 inhibitor, which showed highly potent and selective ACC1 inhibition as well as acceptable solubility and CYP inhibition profiles. Since compound 1q displayed favorable bioavailability in mouse cassette dosing testing, we conducted in vivo PD studies of this compound. Oral administration of 1q significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at doses of more than 30 mg/kg. Accordingly, our novel series of selective ACC1 inhibitors represents a set of useful orally available research tools, as well as potential therapeutic agents for cancer and fatty acid related diseases.
Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Animals , Chemical Phenomena , HCT116 Cells , Humans , Inhibitory Concentration 50 , Mice , Mice, Nude , Structure-Activity RelationshipABSTRACT
A lead compound A was identified previously as an stearoyl coenzyme A desaturase (SCD) inhibitor during research on potential treatments for obesity. This compound showed high SCD1 binding affinity, but a poor pharmacokinetic (PK) profile and limited chemical accessibility, making it suboptimal for use in anticancer research. To identify potent SCD1 inhibitors with more promising PK profiles, we newly designed a series of 'non-spiro' 4, 4-disubstituted piperidine derivatives based on molecular modeling studies. As a result, we discovered compound 1a, which retained moderate SCD1 binding affinity. Optimization around 1a was accelerated by analyzing Hansch-Fujita and Hammett constants to obtain 4-phenyl-4-(trifluoromethyl)piperidine derivative 1n. Fine-tuning of the azole moiety of 1n led to compound 1o (T-3764518), which retained nanomolar affinity and exhibited an excellent PK profile. Reflecting the good potency and PK profile, orally administrated compound 1o showed significant pharmacodynamic (PD) marker reduction (at 0.3mg/kg, bid) in HCT116 mouse xenograft model and tumor growth suppression (at 1mg/kg, bid) in 786-O mouse xenograft model. In conclusion, we identified a new series of SCD1 inhibitors, represented by compound 1o, which represents a promising new chemical tool suitable for the study of SCD1 biology as well as the potential development of novel anticancer therapies.
Subject(s)
Antineoplastic Agents/chemistry , Enzyme Inhibitors/chemical synthesis , Oxadiazoles/chemical synthesis , Pyridazines/chemical synthesis , Stearoyl-CoA Desaturase/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Colonic Neoplasms/drug therapy , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , HCT116 Cells , Humans , Inhibitory Concentration 50 , Mice , Mice, Inbred BALB C , Mice, Nude , Microsomes, Liver/metabolism , Oxadiazoles/pharmacokinetics , Oxadiazoles/therapeutic use , Oxadiazoles/toxicity , Piperidines/chemistry , Piperidines/metabolism , Piperidines/pharmacology , Protein Binding , Pyridazines/pharmacokinetics , Pyridazines/therapeutic use , Pyridazines/toxicity , Spiro Compounds/chemistry , Stearoyl-CoA Desaturase/metabolism , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
We describe a methodology for quick development of fluorescent probes with the desired potency for the target of interest by using a method of parallel synthesis, termed as Parallel Fluorescent Probe Synthesis (Parallel-FPS). BODIPY FL propionic acid 1 is a widely used fluorophore, but it is difficult to prepare a large amount of 1, which hinders its use in parallel synthesis. Optimization of a synthetic scheme enabled us to obtain 50g of 1 in one batch. With this large quantity of 1 in hand, we performed Parallel-FPS of BODIPY FL-labeled ligands for estrogen related receptor-α (ERRα). An initial trial of the parallel synthesis with various linkers provided a potent ligand for ERRα (Reporter IC50=80nM), demonstrating the usefulness of Parallel-FPS.
