Drugs in Clinical Pipeline: GRC 27864 | Microsomal Prostaglandin E Synthase-1 (mPGES-1) Inhibitor | Treatment for Chronic Inflammatory Diseases

GRC 27864 is a potent, selective, orally bioavailable inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1). Prostaglandins (PGs) are an important class of lipids related both to physiological and pathological conditions. Among them, prostaglandin E2 (PGE2) is a key mediator of inflammation, pain and fever, but it is also important for the protection of the gastrointestinal mucosa, nutriuresis, blood pressure regulation, and ovulation.

Microsomal prostaglandin E2 synthase-1 (mPGES-1) catalyzes the terminal step of prostaglandin E2 (PGE2) generation. mPGES-1 is strongly upregulated in inflamed tissues and overexpressed in tumors. mPGES-1 inhibitors may be safer anti-inflammatory agents overcoming the side effects of NSAIDs and COX-2 inhibitors.

Drugs in Clinical Pipeline: PH-797804 | MAPK14 (p38 alpha) Kinase Inhibitor | Anti-inflammatory Drugs

PH-797804 [(aS)-3-{3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl}-N,4-dimethylbenzamde] is an oral, highly potent, selective and metabolically stable p38 mitogen-activated protein (MAP) kinase (MAPK14) inhibitor. In the kinase activity assay PH-797804 inhibits recombinant p38α kinase with an IC₅₀ value of 16 nM, showing 110-fold selectivity over p38β kinase (IC₅₀ value of 107 nM) [1, 2].

Structure of PH-797804 and its atropisomers 

Chemically, PH-797804 is diarylpyridinone scaffold bearing inhibitor of p38 mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS). Computational studies first proposed the existence two atropisomers due to the steric bulk of the pyridinone carbonyl and the 6- and 6’-methyl substituents of racemic molecule. Chiral chromatography of racemate resolved into two atropisomers, PH-797804 (aS) and PH-797805 (aR).

Drugs in Clinical Pipeline: PF-4693627 | Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) Inhibitor | Treatment for Inflammation

PF-4693627 [1-(5-chloro-6-(4-chlorophenyl)benzo[d]oxazol-2-yl)-N-((1S,3S)-3-(hydroxymethyl)cyclohexyl)piperidine-4-carboxamide] is a small molecule, orally bioavailable and selective inhibitor of microsomal prostaglandin E₂ synthase-1 (mPGES-1). Inhibition of mPGES-1, the terminal enzyme in the arachidonic acid/COX pathway to regulate the production of pro-inflammatory prostaglandin PGE₂, is considered an attractive new therapeutic target for safe and effective anti-inflammatory drugs [1, 2].

PF-4693627 : 2D and 3D Structure

Chemically, PF-4693627 is a member of benzoxazole family and displayed good anti-inflammatory activity in various test models. Moreover, the selectivity of PF-4693627 was profiled against several relevant human targets in the following assays: (a) HWB/1483 for selectivity against TXAS, PGDS, 5-LOX, 15-LOX and 12-LOX; (b) Human fetal fibroblasts for selectivity against COX-2. The data show that PF-4693627 is selective for microsomal prostaglandin E₂ synthase-1 (mPGES-1) against relevant human enzymes. PF-4693627 was also submitted to a broad panel screen (CEREP) and no significant findings were observed.


Microsomal Prostaglandin E Synthase-1 (mPGES-1) as Anti-inflammatory Target:

Microsomal prostaglandin E synthase-1 (mPGES-1) belongs to the membrane-associated proteins involved in eicosanoid and glutathione metabolism (MAPEG) super family. It is the terminal enzyme in the metabolism of arachidonic acid (AA) via the cyclooxygenase (COX) pathway (particularly COX-2), responsible for the conversion of prostaglandin H₂ (PGH₂) to a more stable product prostaglandin E₂ (PGE₂). As PGE₂ is a key mediator of pain and inflammation, the enhanced mPGES-1 expression is associated with many pathological conditions in humans; including rheumatoid arthritis (RA), osteoarthritis (OA), inflammatory bowel disease (IBD), cancer etc [1 - 3].

The biosynthesis of PGE₂ begins with the cleavage of arachidonic acid (AA) from membrane phospholipids by phospholipase A₂, followed by the conversion of AA to PGH₂ by cyclooxygenase (COX), and finally to the production of PGE₂ by PGE synthase (PGES). Three forms of PGES have been reported: cytosolic PGES (cPGES), microsomal PGES-1 (mPGES-1), and microsomal PGES-2 (mPGES-2). Both cPGES and mPGES-2 are constitutively expressed in a variety of tissues, while mPGES-1 is up-regulated under inflammatory conditions.

For patients with inflammatory pain caused by osteoarthritis (OA) and rheumatoid arthritis (RA), the first line of treatment is nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors (COXIBs). The COXIBs are superior to NSAIDs due to their lower incidence of GI side effects, but they are no more effective in symptom remission than NSAIDs and safety issues have surfaced, including renal toxicity and increased cardiovascular risk. A selective inhibitor of mPGES-1 would be expected to inhibit PGE₂ production induced by inflammation while sparing constitutive PGE₂, prostacyclin (PGI₂), and thromboxane production. This selectivity should differentiate mPGES-1 inhibitors from NSAIDS and COX-2 inhibitors in the treatment of inflammation and arthritis.

Mechanism of Action in PF-4693627:

PF-4693627 is an orally available and highly selective microsomal prostaglandin E₂ synthase-1 (mPGES-1) inhibitor. PF-4693627 is also species selective, as it only inhibits human mPGES-1 (IC₅₀ = 0.003 µM). PF-4693627 inhibits PGE₂ synthesis in a human whole blood assay without interfering with PGD₂, thromboxane or leukotriene synthesis. It was shown to inhibit PGE₂ synthesis in vivo in the guinea pig air pouch model of acute inflammation [1, 2].

Dosages and Approvals:

PF-4693627 (Tradename: -) is discovered and being developed at Pfizer. It is first microsomal prostaglandin E₂ synthase-1 (mPGES-1) inhibitor selected as a clinical candidate for the treatment of inflammation caused by rheumatoid arthritis (RA) and osteoarthritis (OA).

Reported Activities for PF-4693627:

PF-4693627 was identified as a very potent inhibitor of microsomal prostaglandin E2 synthase-1 (mPGES-1; IC₅₀ = 3 nM) with comparable potency in a fetal fibroblast cell assay (mPGES-1 IC₅₀ = 6 nM). Moreover, the compound showed good activity in human whole blood (HWB) cell-based assay (IC₅₀ = 109 nM).

The selectivity of PF-4693627 was profiled against several relevant human targets in the following assays: (a) HWB/1483 for selectivity against TXAS, PGDS, 5-LOX, 15-LOX and 12-LOX (IC₅₀ greater than 50 uM); (b) Human fetal fibroblasts for selectivity against COX-2 (IC₅₀ greater than 10 uM).

IC₅₀ (Inhibition of mPGES-1 activity) = 3 nM

IC₅₀ (Inhibition of mPGES-1 activity in HWB cells) = 109 nM

IC₅₀ (Inhibition of mPGES-1 activity in fetal fibroblast cells) = 6 nM

IC₅₀ (Inhibition of mPGES-1 activity in HWB-1483 cells) = 180 nM

Summary

Common name: PF-4693627; PF4693627; PF 4693627

Trademarks: -

Molecular Formula: C26H29Cl2N3O3

CAS Registry Number: 1312815-93-2

CAS Name: 1-(5-chloro-6-(4-chlorophenyl)benzo[d]oxazol-2-yl)-N-((1S,3S)-3-(hydroxymethyl)cyclohexyl)piperidine-4-carboxamide

Molecular Weight: 502.43

SMILES:OC[C@H]1CCC[C@H](NC(C(CC2)CCN2C3=NC4=CC(Cl)=C(C5=CC=C(Cl)C=C5)C=C4O3)=O)C1

InChI Key: CPDNPVKDQXLYHO-JXFKEZNVSA-N

InChI: InChI=1S/C26H29Cl2N3O3/c27-19-6-4-17(5-7-19)21-13-24-23(14-22(21)28)30-26(34-24)31-10-8-18(9-11-31)25(33)29-20-3-1-2-16(12-20)15-32/h4-7,13-14,16,18,20,32H,1-3,8-12,15H2,(H,29,33)/t16-,20-/m0/s1

Mechanism of Action: Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) Inhibitor

Activity: Treatment for Inflammation; Anti-inflammation Agents

Status: Preclinical

Chemical Class: Small molecules; Chlorine containing; Amides; Piperidine containing; Chlorobenzenes; Benzoxazole derivatives

Originator: Pfizer

PF-4693627 Synthesis

WO2011077313A1: The patent reports synthesis of PF-4693627 and all the intermediates involved. Also see Ref 1 and 2.

Synthesis of PF-4693627

Identifications:

1H NMR (Estimated) for PF-4693627

Experimental: ¹H NMR (400 MHz, METHANOL-c₄) δ 1 .16 - 1 .29 (m, 1 H), 1 .38 - 1.48 (m, 1 H), 1.55 - 1.62 (m, 4 H), 1 .64 - 1.73 (m, 2 H), 1.75 - 1.92 (m, 5 H), 2.50 - 2.63 (m, 1 H), 3.16 - 3.27 (m, 2 H), 3.44 (d, J = 6.83 Hz, 2 H), 3.96 - 4.03 (m, 1 H), 4.26 - 4.35 (m, 2 H), 7.32 (s, 1 H), 7.35 (s, 1 H), 7.38 - 7.46 (m, 4 H).

Sideeffects: Nothing reported.

Others:

1. Discovery of PF-4693627: PF-9184 [N-(3’, 4’-dichlorobiphenyl-4-yl)-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide] is the first mPGES-1 selective inhibitor generated at Pfizer. Chemically, PF-9184 bears an oxicam template and has an IC₅₀ of 0.016 µM for mPGES-1. Its selectivity however, was only tested against recombinant COX enzymes. It was mainly used to characterize the impact of mPGES-1 inhibition on the prostanoid profile in cultures of synovial fibroblasts from RA patients, in which it causes a shunt of PGH₂ to the prostacylin pathway in a short incubation assay, but a reduction in both PGE₂ and 6-keto PGF1α in a long incubation assay. An inhibition of prostacyclin synthase can thus be ruled out, but it remains unclear whether PF-9184 has an inhibitory potential on the other prostanoid synthases. PF-9184 has poor aqueous solubility and attempts to improve this property unequivocally led to loss of potency. PF-9184 is inactive on rat mPGES-1 [4, 5].

Early Inhibitors of mPGES-1

Screening of the Pfizer compound collection identified compound 1 as a modest inhibitor of human mPGES-1, with an IC₅₀ = 1.2 uM. Short listing of other, related benzoxazoles through similarity and substructure searching of the Pfizer collection led to the discovery of compound 2, which has increased potency (IC₅₀ = 0.85 uM) and selectivity for mPGES-1 (PGE₂) over COX-2 (PGF2 α) in an IL-1 stimulated fetal fibroblast cell assay (PGE₂ IC₅₀ = 1.01 uM; PGF2α IC₅₀ greater than 100 uM). Compound 2 offers several positive attributes, including low molecular weight and clogP, which allow significant changes to the structure without destroying its drug-like character. Compound 2 is stable to human liver microsomes and is predicted by the Pampa assay to have high permeability; a drawback is that it displays high protein binding (99.5%), which negatively impacts its efficacy in whole blood assays. Compound 3 displays mPGES-1 inhibition of 0.018 uM and selectivity over COX-2 in the human fetal fibroblast cell assay. It inhibits PGE2 production in the LPS/human whole blood assay with an IC₅₀ of nearly 7 uM, with the discrepancy between enzymatic and whole blood assays due to the high protein binding of the molecule.  It is predicted to show poor permeability and is highly metabolized in rat and human microsomes with a very short half-life in both species. However, the results were better in a dog PK study, possibly due to differences in plasma protein binding across species [1, 2].

References:

1. Nugent, R. A.; et. al. Novel benzoxazole inhibitors of mPGES-1. Bioorg Med Chem Lett 2013, 23(3), 907 - 911. (FMO)

2. Arhancet, G. B.; et. al. Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation. Bioorg Med Chem Lett  2013, 23(4), 1114 - 1119. (FMO)

3. Koeberle, A.; et. al. Design and Development of Microsomal Prostaglandin E2 Synthase-1 Inhibitors: Challenges and Future Directions. J Med Chem 2016, 59(13), 5970 - 5986. (FMO)

4. Mbalaviele, G.; et. al. Distinction of microsomal prostaglandin E synthase-1 (mPGES-1) inhibition from cyclooxygenase-2 inhibition in cells using a novel, selective mPGES-1 inhibitor. Biochem Pharmacol 2010, 79(10), 1445 - 1454. (FMO)

5. Wang, J.; et. al. Selective inducible microsomal prostaglandin E(2) synthase-1 (mPGES-1) inhibitors derived from an oxicam template. Bioorg Med Chem Lett 2010, 20(5), 1604 - 1609. (FMO)

6. Springer, J. R.; et. al. Piperidinecarboxamides as mpges - 1 inhibitors. WO2011077313A1

1 2 3

Drugs in Clinical Pipeline: Cabiralizumab | Monoclonal Antibodies (mAbs) | Cancer Treatment | Anti-Inflammatory Agents | Anti-CSF1R Antibody

Cabiralizumab (also known as FPA008) is a humanized IgG4 monoclonal antibody that binds to human colony stimulating factor 1 receptor (CSF1R), and blocks the ability of IL34 and CSF1 to activate CSF1R expressed on macrophages. Cabiralizumab specifically targets macrophages and monocytes, immune cells that are activated or elevated in multiple disease settings [1, 2].

Drugs in Clinical Pipeline: THR-317 I Monoclonal Antibody (mAbs) I Angiogenesis Inhibitors | Placenta Growth Factor (PIGF) Inhibitors | Eye Disorder Therapies

THR-317 (also known as TB-403; RO5323441; αPIGF) is a humanized recombinant immunoglobulin (Ig) G₁ monoclonal antibody directed to the receptor-binding site of placental growth factor (PlGF). Inhibition of angiogenesis as a therapeutic strategy in oncology has been validated by treatments that block VEGF or its receptors, vascular endothelial growth factor receptor (VEGFR-1, -2, -3). Several antiangiogenesis inhibitors targeting VEGF or its receptors have been approved, such as the monoclonal antibody bevacizumab and the tyrosine kinase inhibitors Sorafenib and Sunitinib [1, 2].

Seratrodast | Thromboxane A2 (TXA2) Receptor Antagonist | Prostaglandin H2 (PGH2) Receptor Antagonist | Treatment of Asthma

Seratrodast [7-Phenyl-7-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)heptanoic acid] is a thromboxane A₂ (TXA₂) receptor {TP receptor} antagonist marketed as an antiasthmatic drug with inhibitory effects on immediate asthmatic reaction in asthma and airway hypersensitivity. It also has antagonistic effects on contractile prostanoids, including PGH₂, PGF_2α, PGD₂, and 11β- PGD₂. Thus this drug is expected to have a wide range of antagonistic effects on bronchoconstriction mediators [1, 2].

2D and 3D Structure for Seratrodast

Chemically, it is a quinone derivative with a long alkyl chain ending in a carboxylic acid, making it poorly soluble in water. It is a chiral molecule, though marketed as a racemate, studies report the best activities in the following order of descent: R–enantiomer, racemate and finally S–enantiomer. It is a novel design, orally active, potent and long acting TP/PGH₂ receptor antagonist.

Body Suppresses Inflammation During Sleep at Night Time

Concept: People have been suffering from morning stiffness for ages. The common feeling is that we sleep absence of pain, but when we wake up things just starting going bad to worse. Though many theories were placed to explain the phenomena of morning stiffness but none is able to explain the observation completely.

In a new research it is proved that biological clock of human body regulated inflammation especially during night sleep. With the help of a protein named Cryptochrome, the body actively represses inflammatory pathways within the affected limbs during the night.

Observations: Researchers from the field of inflammatory diseases have common observations such as:

a: There is strong diurnal variation in the symptoms and severity of chronic inflammatory diseases, such as rheumatoid arthritis.

b: Disruption of the circadian clock is an aggravating factor associated with a range of human inflammatory diseases.

Methodology: In order to investigate the mechanistic links between the biological clock and pathways underlying inflammatory arthritis, an animal model was developed where mice were administered collagen (or saline as a control) to induce arthritis. Furthermore, exposure of mice to constant light was carried to disrupt the clock in peripheral tissues, to record any loss of the nighttime repression of local inflammation.

The salient observations of the study were:

a: The treatment provoked an inflammatory response within the limbs, which showed robust daily variation in paw swelling and inflammatory cytokine expression.

b: Inflammatory markers were significantly repressed during the dark phase.

c: Exposure of mice to constant light disrupted the clock in peripheral tissues, causing loss of the nighttime repression of local inflammation.

Researchers attributed these findings to the ability of protein, called Cryptochrome, which have proven anti-inflammatory effects. Formed by the body's "biological clock" Cryptochrome actively represses inflammatory pathways within the affected limbs during the night.

To double check their findings, the researchers harvested cells from joint tissue of healthy mice called fibroblast-like synoviocytes (FLSs) which are important in the pathology that underlies inflammatory arthritis. Each of these cells keeps a 24-hour rhythm, and when this rhythm was disrupted by knocking out the cryptochrome gene there was an increased inflammatory response. This highlighted that importance of cryptochrome gene product of cryptochrome protein. To test this hypothesis, researchers administered drugs designed to activate the protein to determine if protection against inflammation could be achieved-and it was.

The authors conclude as “that under chronic inflammatory conditions, the clock actively represses inflammatory pathways during the dark phase. This interaction has exciting potential as a therapeutic avenue for treatment of inflammatory disease.”

Article citation: Gibbs, J. E.; et. al. The circadian clock regulates inflammatory arthritis. 2016, doi:10.1096/fj.201600353R

Imrecoxib | NSAID | Treatment of Osteoarthritis | COX-2 Inhibitor

Imrecoxib [4-(4-methane-sulfonyl-phenyl)-1-propyl-3-p-tolyl-1,5-dihydropyrrol-2-one] is a novel and moderately selective cyclooxygenase-2 (COX-2) inhibitor that possesses anti-inflammatory effect by inhibition of COX-2 mRNA expression. It belongs to the family of non-steroid anti-inflammtory drugs (NSAIDs). Imrecoxib was found to inhibit COX-1 and COX-2 with IC₅₀ value of 115 ± 28 nM and 18 ± 4 nM, respectively [1].

Imrecoxib: 2D and 3D Structure

Imrecoxib effectively inhibited carrageenan-induced acute inflammation at the doses of 5, 10, and 20 mg-kg-1 ig and adjuvant-induced chronic inflammation at the doses of 10 and 20 mg-kg -1·d-1 ig.

NSAIDs and Imrecoxib:

Non-steroidal anti-inflammatory drugs (NSAIDs) are used extensively for the treatment of inflammatory conditions, including pain-releasing, anti-pyretic and rheumatoid arthritis. These functions are believed to inhibit the enzyme cyclooxygenase (COX) that is involved in the biosynthesis of prostaglandins G and H from arachidonic acid. So far two isozymes of COX are known: COX-1 and COX-2. COX-1 is constitutively produced in a variety of tissues and appears to be important to the maintenance of normal physiological functions, including gastric and renal cytoprotection. The COX-2 is an inducible isozyme, which is produced in cells under the stimulation of endotoxins, cytokines, and hormones and catalyzes the production of prostaglandins which cause inflammation.


The currently therapeutic use of NSAIDs has been associated with the inhibition of both COX-1 and COX-2 and causes well-known side effects at the gastrointestinal and renal level. Therefore, the selective COX-2 inhibitors could provide anti-inflammatory agents devoid of the undesirable effects associated with classical, nonselective NSAIDs. In addition, COX-2 is over-expressed in colon cancer tissue. COX-2 inhibitors possess potential prophylactic and therapeutic application to colon cancer.

Imrecoxib is designed in a manner such that it has "moderate selectivity" for COX-2 over COX-1.  This balanced inhibition to both COX-1 and COX-2 was pursued to maintain the homeostasis of the two enzymes in the body,which is presumably critical to normal functions of the cardiovascular system.

Imrecoxib was launched in China with the trade name of Hengyang for the treatment of osteoarthritis in May 2011. Hengyang  is available as tablet for oral use, containing 100 mg of free Imrecoxib, and the recommend dose is 100 mg twice daily.

Summary Sheet

Common name: Imrecoxib; BAP-909; BAP 909; BAP909
Trademarks: Hengyang
Molecular Formula: C21H23NO3S
CAS Registry Number: 395683-14-4
IUPAC Name: 4-(4-methane-sulfonyl-phenyl)-1-propyl-3-p-tolyl-1,5-dihydropyrrol-2-one
Molecular Weight: 369.48
SMILES: O=C1N(CCC)CC(C2=CC=C(S(=O)(C)=O)C=C2)=C1C3=CC=C(C)C=C3
Mechanism: COX-2 Inhibitor; Cyclooxygenase-2 Inhibitor
Activity: Treatment of Osteoarthritis; Analgesic; Antipyritic; Antiinflammatory Drug
Status: Launched 2011 (China)
Originator: HengRui

Imrecoxib Synthesis

Chin Chem Lett 2001, 12, 775-778 (also Ref 2. This route is quoted as industrial method in various texts)

CN104193664A (an improvement here as Br is replaced with Cl)

US7112605B2 (primary reference for synthesis routes)

Identification:

1H NMR (Estimated) for Imrecoxib

Experimental: ¹H-NMR (CDCl₃, TMS, 400MHz) 1.008 (3H, t, J = 7.2Hz), 1.701-1.756 (2H, m), 2.376 (3H, s), 3.078 (3H, s), 3.575 (2H, t, J = 7.2Hz), 4.317 (2H, s), 7. 175 (2H, d, J = 8.0Hz), 7.294 (2H, d, J = 8.0Hz), 7.505 (2H, t, J = 6.8Hz), 7.870 (2H, t, J = 6.8Hz)

Sideeffects:

Being a mild COX-2 inhibitor, it is expected not to cause any serious cardiovascular risks. Similarly, it should not have any serious gastrointestinal problems too, as it not a good inhibitor of COX-1. None of the reports though have listed any serious adverse event reported by patients in the clinical trials.

References:

1. Cheng, G. F.; et. al. Imrecoxib: A novel and selective cyclooxygenase 2 inhibitor with anti-inflammatory effect. Acta Pharmacol Sin 2004, 25(7), 927-931.

2. Zhang, F.; et. al. Method for preparing imrecoxib. CN102206178A

3. Chao, W.; et. al. Synthesis method of imrecoxib. CN104193664A

4. Bai, A. P.; et. al. Synthesis and in vitro Evaluation of a New Class of Novel Cyclooxygenase-2 Inhibitors: 3, 4-diaryl-3-pyrrolin-2 ones. Chin Chem Lett 2001, 12, 775-7785.

5. Guo, Z. Discovery of imrecoxib. Chin J New Drugs 2012, 21, 223.

6. Guo, Z.; et. al. Sulfonyl-containing 3,4-diaryl-3-pyrrolin-2-ones, preparation method, and medical use thereof. US7112605B2

Drugs in Clinical Pipeline: RO-9021

RO-9021 [(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide] is an oral, ATP-competative and selective inhibitor of spleen tyrosine kinase (SYK). RO-9021 potently inhibited SYK kinase activity with an average IC₅₀ of 5.6 nM. Selectivity of RO-9021 against a panel of 451 wild-type and mutant protein kinases was assessed using an ATP binding site competition assay developed by KINOMEscan Inc.  

RO-9021 is a highly selective SYK inhibitor with low S-scores of 0.003 for S(99) and 0.015 for S(90), indicating that SYK is the only kinase with 99% competition with RO-9021 (1 uM) in a total of 392 tested kinases. There were only a total of seven kinases (JAK1, JAK3, GCN2, SLK, FLT3(ITD), PAK2) including SYK, having more than 90% competition with RO9021. It inhibited JAK1 and JAK3 with 97% at 1 uM.

References:

1. Liao, C.; et. al. Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: implications for SYK inhibitors in autoimmune disease therapy. Arthritis Res Ther 2013, 15(5), R146.

Drugs in Clinical Pipeline: GSK143

GSK143 [2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide] is a potent and highly selective spleen tyrosine kinase (SYK) inhibitor (pIC₅₀ = 7.5) showing good efficacy in the rat Arthus model. The selectivity profile of GSK143 was determined against a panel of 66 protein kinases and none were inhibited within 10-fold of SYK activity. GSK143 is greater than 600-fold selective for SYK over ZAP-70 (pIC₅₀ = 4.7), the other member of the SYK kinase family [1].

The activity of GSK143 is as follows:

pIC₅₀(SYK enzyme assay) = 7.5

pIC₅₀(ZAP-70 enzyme assay) = 4.7

pIC₅₀(LCK enzyme assay) = 5.3

pIC₅₀(LYN enzyme assay) = 5.4

pIC₅₀(JAK1 enzyme assay) = 5.8

pIC₅₀(JAK2 enzyme assay) = 5.8

pIC₅₀(JAK3 enzyme assay) = 5.7

pIC₅₀(AURKB enzyme assay) = 4.8

Common Name: GSK143

Synonyms: GSK143; GSK-143; GSK 143

IUPAC Name: 

CAS Number: 1240390-27-5

SMILES:

Mechanism of Action: Kinase Inhibitor; SYK Inhibitor; Spleen Kinase Inhibitor

Indication: Various Cancers; Anti-inflammatory Drugs

Development Stage: Investigational

Company: GlaxoSmithKline

The progression of GSK143 was terminated due to a mutagenicity risk highlighted in the Ames assay, it remains one of the most selective SYK inhibitors disclosed to date and hence an excellent tool molecule for further evaluation of the SYK mechanism.

References:
1. Liddle, J.; et. al. Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor. Bioorg Med Chem Lett 2011, 21(20), 6188-6194.