Delving into the Latest Updates on PF-05175157 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

ACC

Mechanism

ACC inhibitors(Acetyl-CoA carboxylase inhibitors)

Therapeutic Areas

Endocrinology and Metabolic DiseaseSkin and Musculoskeletal Diseases

Active Indication-

Inactive Indication

Acne VulgarisDiabetes Mellitus, Noninsulin-Dependent, 2Diabetes Mellitus, Type 2+ [1]

Originator Organization

Pfizer Inc.

Active Organization-

Inactive Organization

Pfizer Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC23H27N5O2

InChIKeyBDXXSFOJPYSYOC-UHFFFAOYSA-N

CAS Registry1301214-47-0

Acetyl-CoA carboxylase (ACC) plays a regulatory role in both fatty acid synthesis and oxidation, controlling the process of lipid deposition in the liver. Given that existing studies have shown a close relationship between low phosphorus (P) and hepatic lipid deposition, this study was conducted to investigate whether ACC plays a crucial role in this relationship. Zebrafish liver cell line (ZFL) was incubated under low P medium (LP, P concentration: 0.77 mg/L) or adequate P medium (AP, P concentration: 35 mg/L) for 240 h. The results showed that, compared with AP-treated cells, LP-treated cells displayed elevated lipid accumulation, and reduced fatty acid β-oxidation, ATP content, and mitochondrial mass. Furthermore, transcriptomics analysis revealed that LP-treated cells significantly increased lipid synthesis (Acetyl-CoA carboxylases (acc), Stearyl coenzyme A dehydrogenase (scd)) but decreased fatty acid β-oxidation (Carnitine palmitoyltransferase I (cptI)) and (AMP-activated protein kinase (ampk)) mRNA levels compared to AP-treated cells. The phosphorylation of AMPK and ACC, and the protein expression of CPTI were significantly decreased in LP-treated cells compared with those in AP-treated cells. After 240 h of LP treatment, PF-05175157 (an ACC inhibitor) was supplemented in the LP treatment for an additional 12 h. PF-05175157-treated cells showed higher phosphorylation of ACC, higher protein expression of CPTI, and lower protein expression of FASN, lower TG content, enhanced fatty acid β-oxidation, increased ATP content, and mitochondrial mass compared with LP-treated cells. PF-05175157 also relieved the LP-induced oxidative stress and inflammatory response. Overall, these findings suggest that ACC is a promising target for treating LP-induced elevation of lipid deposition in ZFL, and can alleviate oxidative stress and inflammatory response.

28 Jan 2021·Toxicological Sciences

Inhibition of Acetyl-CoA Carboxylase Causes Malformations in Rats and Rabbits: Comparison of Mammalian Findings and Alternative Assays

Article

Author: Cappon, Gregg D ; Nowland, William S ; Campion, Sarah N ; Bowman, Christopher J ; Lewis, Elise M ; Ross, Trenton T ; Esler, William P ; Catlin, Natasha R ; Kumpf, Steven W ; Davenport, Scott D ; Stedman, Donald S ; Stethem, Christine

AbstractAcetyl-CoA carboxylase (ACC) is an enzyme within the de novo lipogenesis (DNL) pathway and plays a role in regulating lipid metabolism. Pharmacologic ACC inhibition has been an area of interest for multiple potential indications including oncology, acne vulgaris, metabolic diseases such as type 2 diabetes mellitus, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. A critical role for ACC in de novo synthesis of long-chain fatty acids during fetal development has been demonstrated in studies in mice lacking Acc1, where the absence of Acc1 results in early embryonic lethality. Following positive predictions of developmental toxicity in the alternative in vitro assays (positive in murine embryonic stem cell [mESC] assay and rat whole embryo culture, but negative in zebrafish), developmental toxicity (growth retardation and dysmorphogenesis associated with disrupted midline fusion) was observed with the oral administration of the dual ACC1 and 2 inhibitors, PF-05175157, in Sprague Dawley rats and New Zealand White rabbits. The results of these studies are presented here to make comparisons across the assays, as well as mechanistic insights from the mESC assay demonstrating high ACC expression in the mESC and that ACC-induced developmental toxicity can be rescued with palmitic acid providing supportive evidence for DNL pathway inhibition as the underlying mechanism. Ultimately, while the battery of alternative approaches and weight-of-evidence case were useful for hazard identification, the embryo-fetal development studies were necessary to inform the risk assessment on the adverse fetal response, as malformations and/or embryo-fetal lethality were limited to doses that caused near-complete inhibition of DNL.

08 Oct 2020·Journal of Medicinal ChemistryQ1 · MEDICINE

Optimizing the Benefit/Risk of Acetyl-CoA Carboxylase Inhibitors through Liver Targeting

Q1 · MEDICINE

Article

Author: Bagley, Scott W. ; El-Kattan, Ayman ; Huard, Kim ; Smith, Aaron C. ; Dowling, Matthew S. ; Crowley, Collin ; Price, David A. ; Thuma, Benjamin A. ; Smith, Andrew H. ; Niosi, Mark ; Mascitti, Vincent ; Liras, Spiros ; Bi, Yi-An ; Doran, Shawn D. ; Griffith, David A. ; Southers, James R. ; Cabral, Shawn ; Esler, William P. ; Shavnya, Andre ; Varma, Manthena V. ; Shirai, Norimitsu ; Fernando, Dilinie P. ; Tess, David A. ; Pfefferkorn, Jeffrey A. ; Cappon, Gregg ; Edmonds, David J. ; Polivkova, Jana ; Beebe, David ; Ross, Trenton T. ; Yang, Xiaojing ; Préville, Cathy ; Dow, Robert L. ; Kalgutkar, Amit S.

Preclinical and clinical data suggest that acetyl-CoA carboxylase (ACC) inhibitors have the potential to rebalance disordered lipid metabolism, leading to improvements in nonalcoholic steatohepatitis (NASH). Consistent with these observations, first-in-human clinical trials with our ACC inhibitor PF-05175157 led to robust reduction of de novo lipogenesis (DNL), albeit with concomitant reductions in platelet count, which were attributed to the inhibition of fatty acid synthesis within bone marrow. Herein, we describe the design, synthesis, and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 (12), which selectively inhibits liver DNL in animals, while demonstrating considerable safety margins against platelet reduction in a nonhuman primate model.

100 Deals associated with PF-05175157

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12096

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acne Vulgaris	Phase 2	-	Pfizer Inc.	01 Apr 2014
Diabetes Mellitus, Type 2	Phase 2	US	Pfizer Inc.	01 Dec 2012
Obesity	Phase 2	US	Pfizer Inc.	01 Oct 2012
Diabetes Mellitus, Noninsulin-Dependent, 2	Phase 2	US	Pfizer Inc.	01 Jul 2011

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01792635 (CTgov)	Phase 2	Diabetes Mellitus, Type 2	19	insulin (All Participants in Part A)	sredpwiegm(vsrovmhlfk) = eoiltzqycp omijcveowo (slahyllfma, yhkkdhtnhn - fqjnggqzoc) View more	-	16 Feb 2017
				Placebo (Placebo - Part B)	lyyqkiqkfj(cxqxqiwrpw) = mkskydfgsd ierwjmpgho (cyrksuzwli, ixlcopvcrc - mwdcynwaiu) View more
NCT01396161 (CTgov)	Phase 1	Diabetes Mellitus, Noninsulin-Dependent, 2	64	Placebo (Placebo - HOV)	(crdvwjadep) = anxevlfodi lhmkrrtrnc (cravuhikyu, kqeayzuqii - njhkoyairl) View more	-	06 Nov 2016
				Placebo (Placebo - T2DM)	(crdvwjadep) = lwlssyzpfn lhmkrrtrnc (cravuhikyu, rfcylldanl - fnveqaeqev) View more
NCT01819922 (CTgov)	Phase 1	-	12	Placebo	wclbvnzhdr(atiugizkko) = ksamjewhff vaxnbsfmmt (rwtsxzzrrg, kpfywnlzra - tmpcdqjdoy) View more	-	02 May 2016