Monday, January 2, 2017

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].

Stucture of PF-4693627
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


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
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
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