Trial reportJournal of medicinal chemistry2014
Decreasing the rate of metabolic ketone reduction in the discovery of a clinical acetyl-CoA carboxylase inhibitor for the treatment of diabetes.
Trial report in Journal of medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
31 citing papers in PubMed, 88 citations in OpenAlex.
- ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials.Nature medicine · 2021Trial
- De novo lipogenesis is essential for platelet production in humans.Nature metabolism · 2020Trial
- Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Liver-Targeting Acetyl-CoA Carboxylase Inhibitor (PF-05221304): A Three-Part Randomized Phase 1 Study.Clinical pharmacology in drug development · 2020Trial
- Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double-blind, crossover study.Hepatology (Baltimore, Md.) · 2017Trial
- Fatty acid synthesis restricts HIV-1 infection through regulation of the nuclear envelope in CD4+ T cells.bioRxiv : the preprint server for biology · 2026Article
- Research progress and therapeutic strategies in hepatocellular carcinoma metabolic reprogramming.Journal of advanced research · 2026Review
- Superstable lipid vacuoles endow cartilage with its shape and biomechanics.Science (New York, N.Y.) · 2025Article
- Pharmacologic inhibition of lipogenesis for the treatment of NAFLD.Journal of hepatology · 2024Review
- Mitochondrial fatty acid beta-oxidation: a possible therapeutic target for skeletal muscle lipotoxicity in peripheral artery disease myopathy.EXCLI journal · 2024Review
- Testosterone with Silymarin Improves Diabetes-obesity Comorbidity Complications by Modulating Inflammatory Responses and CYP7A1/ACC Gene Expressions in Rats.Combinatorial chemistry & high throughput screening · 2024Article
- Role of AMPK-SREBP Signaling in Regulating Fatty Acid Binding-4 (FABP4) Expression following Ethanol Metabolism.Biology · 2022Article
- Advances and Emerging Therapies in the Treatment of Non-alcoholic Steatohepatitis.TouchREVIEWS in endocrinology · 2022Review
- Comprehensive Analysis of Metabolic Isozyme Targets in Cancer.Cancer research · 2022Article
- Lipogenesis inhibitors: therapeutic opportunities and challenges.Nature reviews. Drug discovery · 2022Review
- Acetyl-CoA Carboxylases and Diseases.Frontiers in oncology · 2022Review
- Acetyl-CoA Carboxylase Inhibitor CP640.186 Increases Tubulin Acetylation and Impairs Thrombin-Induced Platelet Aggregation.International journal of molecular sciences · 2021Article
- Synthesis and biological evaluation of 4-phenoxy-phenyl isoxazoles as novel acetyl-CoA carboxylase inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2021Article
- Metabolic drivers of non-alcoholic fatty liver disease.Molecular metabolism · 2021Review
- High Fat Activates O-GlcNAcylation and Affects AMPK/ACC Pathway to Regulate Lipid Metabolism.Nutrients · 2021Article
- Photochemical Methods for Peptide Macrocyclisation.Chemistry (Weinheim an der Bergstrasse, Germany) · 2021Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
18 authors at 3 institutions in 1 country.
Funding
Abstract
Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections. We disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly basic functionality improved solubility and led to the identification of 9 as a clinical candidate for the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. This demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.