PF-04991532 | PF-4991532 | CAS#1215197-37-7 | hepatoselective glucokinase activator

MedKoo Cat#: 522525 | Name: PF-04991532

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Description:

WARNING: This product is for research use only, not for human or veterinary use.

PF-04991532 is a potent and selective hepatoselective glucokinase activator. PF-04991532 ameliorates hyperglycemia without causing hepatic steatosis in diabetic rats. F-04991532 reduced plasma glucose concentrations independent of changes in insulin concentrations in a dose-dependent manner both acutely and after 28 days of sub-chronic treatment. PF-04991532 may offer glycemic control without inducing hepatic steatosis supporting the evaluation of tissue specific activators in clinical trials.

Chemical Structure

PF-04991532

CAS#1215197-37-7

Theoretical Analysis

MedKoo Cat#: 522525

Name: PF-04991532

CAS#: 1215197-37-7

Chemical Formula: C18H19F3N4O3

Exact Mass: 396.1409

Molecular Weight: 396.37

Elemental Analysis: C, 54.54; H, 4.83; F, 14.38; N, 14.14; O, 12.11

Price and Availability

Size	Price	Availability	Quantity
5mg	USD 425.00	2 Weeks
25mg	USD 775.00	2 Weeks

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Related CAS #

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Synonym

PF-04991532; PF 04991532; PF04991532; PF-4991532; PF4991532; PF 4991532.

IUPAC/Chemical Name

(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid

InChi Key

GKMLFBRLRVQVJO-ZDUSSCGKSA-N

InChi Code

InChI=1S/C18H19F3N4O3/c19-18(20,21)14-9-25(10-23-14)13(7-11-3-1-2-4-11)16(26)24-15-6-5-12(8-22-15)17(27)28/h5-6,8-11,13H,1-4,7H2,(H,27,28)(H,22,24,26)/t13-/m0/s1

SMILES Code

O=C(O)C1=CN=C(NC([C@@H](N2C=C(C(F)(F)F)N=C2)CC3CCCC3)=O)C=C1

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

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Product Data

Product Data

Instruction

View handling instruction

Biological target:

PF-04991532 is a potent, hepatoselective glucokinase activator with EC50s of 80 and 100 nM in human and rat, respectively.

In vitro activity:

TBD

In vivo activity:

In these studies, PF-04991532 reduced plasma glucose concentrations independent of changes in insulin concentrations in a dose-dependent manner both acutely and after 28 days of sub-chronic treatment. During a hyperglycemic clamp in Goto-Kakizaki rats, the glucose infusion rate was increased approximately 5-fold with PF-04991532. This increase in glucose infusion can be partially attributed to the 60% reduction in endogenous glucose production. While PF-04991532 induced dose-dependent increases in plasma triglyceride concentrations it had no effect on hepatic triglyceride concentrations in Goto-Kakizaki rats. Interestingly, PF-04991532 decreased intracellular AMP concentrations and increased hepatic futile cycling. Reference: PLoS One. 2014 May 23;9(5):e97139. https://pubmed.ncbi.nlm.nih.gov/24858947/

	Solvent	mg/mL	mM	comments
Solubility
	DMSO	125.0	315.36

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 396.37 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

Erion DM, Lapworth A, Amor PA, Bai G, Vera NB, Clark RW, Yan Q, Zhu Y, Ross TT, Purkal J, Gorgoglione M, Zhang G, Bonato V, Baker L, Barucci N, D'Aquila T, Robertson A, Aiello RJ, Yan J, Trimmer J, Rolph TP, Pfefferkorn JA. The hepatoselective glucokinase activator PF-04991532 ameliorates hyperglycemia without causing hepatic steatosis in diabetic rats. PLoS One. 2014 May 23;9(5):e97139. doi: 10.1371/journal.pone.0097139. PMID: 24858947; PMCID: PMC4032240.

In vitro protocol:

TBD

In vivo protocol:

1: Ford BE, Chachra SS, Alshawi A, Brennan A, Harnor S, Cano C, Baker DJ, Smith DM, Fairclough RJ, Agius L. Chronic glucokinase activator treatment activates liver Carbohydrate response element binding protein and improves hepatocyte ATP homeostasis during substrate challenge. Diabetes Obes Metab. 2020 Nov;22(11):1985-1994. doi: 10.1111/dom.14111. Epub 2020 Jul 7. PMID: 32519798. 2: Bergman A, Bi YA, Mathialagan S, Litchfield J, Kazierad DJ, Pfefferkorn JA, Varma MVS. Effect of Hepatic Organic Anion-Transporting Polypeptide 1B Inhibition and Chronic Kidney Disease on the Pharmacokinetics of a Liver- Targeted Glucokinase Activator: A Model-Based Evaluation. Clin Pharmacol Ther. 2019 Oct;106(4):792-802. doi: 10.1002/cpt.1419. Epub 2019 Apr 8. PMID: 30919935. 3: Sharma R, Bergman A, Litchfield J, Atkinson K, Kazierad DJ, Kalgutkar AS. Metabolism and excretion of (S)-6-(3-cyclopentyl-2-(4-trifluoromethyl)-1< i>H-imidazol-1-yl)propanamido)nicotinic acid (PF-04991532), a hepatoselective glucokinase activator, in humans: confirmation of the MIST potential noted in first-in-Human metabolite scouting studies. Xenobiotica. 2019 Dec;49(12):1447-1457. doi: 10.1080/00498254.2019.1581960. Epub 2019 Mar 7. PMID: 30747552. 4: Sharma R, Litchfield J, Bergman A, Atkinson K, Kazierad D, Gustavson SM, Di L, Pfefferkorn JA, Kalgutkar AS. Comparison of the circulating metabolite profile of PF-04991532, a hepatoselective glucokinase activator, across preclinical species and humans: potential implications in metabolites in safety testing assessment. Drug Metab Dispos. 2015 Feb;43(2):190-8. doi: 10.1124/dmd.114.061218. Epub 2014 Nov 10. PMID: 25384899. 5: Ghosh A, Maurer TS, Litchfield J, Varma MV, Rotter C, Scialis R, Feng B, Tu M, Guimaraes CR, Scott DO. Toward a unified model of passive drug permeation II: the physiochemical determinants of unbound tissue distribution with applications to the design of hepatoselective glucokinase activators. Drug Metab Dispos. 2014 Oct;42(10):1599-610. doi: 10.1124/dmd.114.058032. Epub 2014 Jul 14. PMID: 25024402. 6: Erion DM, Lapworth A, Amor PA, Bai G, Vera NB, Clark RW, Yan Q, Zhu Y, Ross TT, Purkal J, Gorgoglione M, Zhang G, Bonato V, Baker L, Barucci N, D'Aquila T, Robertson A, Aiello RJ, Yan J, Trimmer J, Rolph TP, Pfefferkorn JA. The hepatoselective glucokinase activator PF-04991532 ameliorates hyperglycemia without causing hepatic steatosis in diabetic rats. PLoS One. 2014 May 23;9(5):e97139. doi: 10.1371/journal.pone.0097139. PMID: 24858947; PMCID: PMC4032240. 7: Pfefferkorn JA, Guzman-Perez A, Litchfield J, Aiello R, Treadway JL, Pettersen J, Minich ML, Filipski KJ, Jones CS, Tu M, Aspnes G, Risley H, Bian J, Stevens BD, Bourassa P, D'Aquila T, Baker L, Barucci N, Robertson AS, Bourbonais F, Derksen DR, Macdougall M, Cabrera O, Chen J, Lapworth AL, Landro JA, Zavadoski WJ, Atkinson K, Haddish-Berhane N, Tan B, Yao L, Kosa RE, Varma MV, Feng B, Duignan DB, El-Kattan A, Murdande S, Liu S, Ammirati M, Knafels J, Dasilva-Jardine P, Sweet L, Liras S, Rolph TP. Discovery of (S)-6-(3-cyclopentyl -2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes mellitus. J Med Chem. 2012 Feb 9;55(3):1318-33. doi: 10.1021/jm2014887. Epub 2012 Jan 24. PMID: 22196621.