Drugs in Clinical Pipeline: SUVN-502 | 5-HT6 receptor antagonist | Treatment for Alzheimer's Disease

SUVN- 502 is a novel, potent, and selective 5-HT₆ receptor antagonist with K_i of 1.71 nM and exhibited antagonist like inhibition with EC₅₀ of 0.103 mM. SUVN-502 is effective in animal models of cognition. In microdialysis studies, SUVN-502 enhanced brain acetylcholine and glutamate levels in rat ventral hippocampus and frontal cortex. SUVN-502 has completed all regulatory safety and toxicity studies.

5-HT₆ receptor a member of serotonin family predominates in brain regions associated with cognition and behavior. The blockade of 5-HT₆ receptors leads to an improvement of cognitive performance in a wide variety of learning and memory paradigms.

Drugs in Clinical Pipeline: CT1812 | Abeta Oligomers Receptor Antagonist | Treatment for Alzheimer's Disease

CT1812, works by a completely novel mechanism to stop the binding of toxic proteins that build up in the brains of Alzheimer's patients known as Abeta oligomers.

CT1812, a novel oligomer receptor antagonist is the only drug candidate that has demonstrated not only prevention but it also displaces binding of Abeta oligomers to receptors on brain cells. By stopping the initiating event in the Abeta oligomer cascade, this first-in-class drug candidate completely blocks downstream synaptotoxicity and restores memory to normal in aged transgenic mouse models of Alzheimer's disease.

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: BI 409306 | PDE9A Inhibitor | Phosphodiesterase 9A Inhibitors | Treatment for Alzheimer's Disease

Phosphodiesterases (PDEs) in the brain have shown to play an important role in synaptic plasticity and cognitive function. Among those PDEs is PDE9A, which specifically regulates the second messenger cGMP in neurons related to NMDA receptor signaling and is expressed in cognition relevant regions of the brain. Thus, PDE9A inhibitors are hypothesized to improve cognitive function via increasing NMDA receptor related cGMP signalling pathway to strengthen synaptic plasticity.

BI 409306 is a potent PDE9A inhibitor, which strengthens synaptic plasticity as demonstrated by increased hippocampal long-term potentiation (LTP). Systemic application of BI 409306 to rats increased cGMP levels in the CSF and brain indicating functional target engagement. Moreover, BI 409306 shows low nanomolar potency against PDE9A.

Drugs in Clinical Pipeline: TRV734 | Treatment of Acute Severe Pain | G Protein-Biased μ-Opioid receptor

TRV734 is novel, potent, and selective G protein-biased μ-opioid receptor ligand. TRV734 robustly engage G protein coupling with efficacy and potency comparable to morphine, but display dramatically reduced β-arrestin coupling. In rodents, TRV734 is potently analgesic, but display reduced gastrointestinal dysfunction (GI) compared to morphine. The improved therapeutic index TRV734 could allow safer, more effective pain management by removing key barriers to effective opioid therapy.

Data from Trevena suggest that oral TRV734 may deliver powerful analgesia with better tolerability than currently used oral opioids for acute and chronic pain.

Drugs in Clinical Pipeline: Oliceridine | Treatment of Acute Severe Pain | G Protein-Biased μ-Opioid receptor

Oliceridine (also known as TRV130) is a G-protein-biased ligand at the μ-opioid receptor. In preclinical studies, it was potently analgesic while causing less respiratory depression and gastrointestinal dysfunction than morphine, suggesting unique benefits in acute pain management. This unique “G protein-biased” μ-opioid ligand is a potent analgesic in rodents, with 3-10 times the potency of morphine, but with reduced gastrointestinal (GI) dysfunction and respiratory depression compared to equianalgesic doses of morphine.

The margin between Oliceridine analgesia and side effects (therapeutic index) in rodents suggests that Oliceridine may be a safer, tolerable analgesic than current parenterally administered opioids such as morphine, fentanyl, and hydromorphone. It is currently in Phase-III trials.

Drugs in Clinical Pipeline: Erenumab | AMG 334 | Prevention of Migraines | CGRP Receptor Antagonist Monoclonal Antibody

Erenumab (AMG 334) is the first human monoclonal antibody antagonist against the Calcitonin Gene-Related Peptide Receptor (CGRP) receptor. Like the small-molecule CGRP-receptor antagonists, Erenumab fully antagonizes CGRP-receptor function and is dose-dependently effective in an in vivo target coverage model that exhibits translatability to humans.

Erenumab fully inhibited CGRP-stimulated cAMP production with an IC₅₀ of 2.3 nM in cell-based functional assays (human CGRP receptor) and was 5000-fold more selective for the CGRP receptor than other human calcitonin family receptors, including adrenomedullin, calcitonin, and amylin receptors.

Drugs in Clinical Pipeline: AL-3778 I Treatment for Hepatitis B Virus (HBV) | Antivirals Agents

AL-3778 (also known as ALS-003778; JNJ-63595948; NVR-1221; NVR-3-778) is an experimental drug being developed by Alios BioPharma, Inc. to treat Hepatitis B virus (HBV) infection . Hepatitis B is an infectious disease caused by the hepatitis B virus which affects the liver. It can cause both acute and chronic infections. The virus is transmitted by exposure to infectious blood or body fluids. Infection around the time of birth or from contact with other people's blood during childhood is the most frequent method by which hepatitis B is acquired in areas where the disease is common. In areas where the disease is rare, intravenous drug use and sexual intercourse are the most frequent routes of infection.

A New Drug for the Treatment for Hepatitis B Virus (HBV)

Drugs in Clinical Pipeline: MCLA-117 | CLEC12AxCD3 Bispecific Immunoglobulin G (IgG) | Bispecific Antibody I Treatment for Acute Myleoid Leukemia (AML)

MCLA-117 is a full length human CLEC12AxCD3 bispecific immunoglobulin G (IgG) that incorporates CH₂ region amino acid substitutions to abrogate Fcγ receptor and C1q interactions while retaining its binding to FcRn. MCLA-117 binds to CD3, a cell-surface molecule present on all T cells, and CLEC12A, a cell surface molecule present on Acute Myleoid Leukemia (AML) cells and stem cells. MCLA-117 is designed to recruit and activate T-cells to kill CLEC12A-expressing AML tumor cells and stem cells, which may prevent recurrence of tumors. MCLA-117 redirects patient's cytotoxic T cells to induce AML tumor lysis.

Drugs in Clinical Pipeline: SC-006 | Treatment of Colorectal Cancer (CRC)

SC-006 is an experimental drug being developed by AbbVie in collaboration with Stemcentrx, for treating patients with advanced colorectal cancer (CRC).

New Drug for Treating Colorectal Cancer

AbbVie, a global biopharmaceutical company, announced in April 2016 that it will acquire Stemcentrx to further boost it’s oncology pipeline. SC-006 is a fruit of the merger. Though the mechanism of action is not revealed, it could be directed against DLL3 (delta-like protein 3) like SC-002.

Drugs in Clinical Pipeline: BMS 986166 | Treatment of Ulcerative Colitis

BMS 986166 is an experimental drug being developed by Bristol-Myers Squibb for treating Ulcerative Colitis (UC). Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptom of active disease is abdominal pain and diarrhea mixed with blood. Weight loss, fever, and anemia may also occur. The cause of UC is unknown. Theories involve immune system dysfunction, genetics, changes in the normal gut bacteria, and environmental factors. Dietary changes may improve symptoms. Several medications are used to treat symptoms and bring about and maintain remission. These include aminosalicylates such as sulfasalazine, steroids, immunosuppressants such as azathioprine, and biological therapy. Removal of the colon by surgery may be necessary if the disease is severe.

New Drug for Treating Ulcerative Colitis

Preclinical development is ongoing, and Phase I development of an oral solution of BMS 986166 is planned in the US [1].

Drugs in Clinical Pipeline: RO7062931 | Treatment of Chronic Hepatitis B Virus | Antivirals Agents

RO7062931 is a new experimental drug being developed by Roche pharma for treating patients with Chronic Hepatitis B. Hepatitis B is an infectious disease caused by the hepatitis B virus (HBV) which affects the liver. It can cause both acute and chronic infections. Many people have no symptoms during the initial infection. The virus is transmitted through contact with the blood or other body fluids of an infected person. An estimated 240 million people are chronically infected with hepatitis B (defined as hepatitis B surface antigen positive for at least 6 months). However, it can be prevented by currently available safe and effective vaccine.

New Drug for Treatment of Chronic Hepatitis B Virus

Drugs in Clinical Pipeline: TAS-116 | Heat Shock Protein (HSP90) Inhibitor | Treatment of Tumors | Cancer Drug

TAS-116 [3-ethyl-4-[3-(1-methylethyl)-4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-1H-pyrazolo[3,4-b]pyridin-1-yl]benzamide] is a small molecule selective heat shock protein 90 (HSP90α/β) inhibitor. It shows greater specific binding to HSP90α and β than to the highly homologous HSP90 family members GRP94 and TRAP1 [1].

TAS-116 : 2D and 3D Structure

Oral administration of TAS-116 led to tumor shrinkage in human tumor xenograft mouse models accompanied by depletion of multiple HSP90 clients, demonstrating that the inhibition of HSP90 α and β alone was sufficient to exert antitumor activity in certain tumor models. One of the most notable HSP90-related adverse events universally observed to differing degrees in the clinical setting is visual disturbance. TAS-116 did not produce detectable photoreceptor injury in rats, probably due to its lower distribution in retinal tissue.

TAS-116 shows favorable pharmacokinetics and a reduced ocular toxicity profile, possibly due to its lower distribution in retinal tissue than in plasma in rats. Moreover, TAS-116 shows superior anti-tumor effects in several tumors including multiple myeloma (MM) and lung carcinoma in vitro and in vivo. TAS-116 represents a novel molecule with promising therapeutic potential [1, 2].

Heat Shock Protein (HSP90) as Drug Target:

Protein folding in the cell is organised by molecular chaperones. The major chaperone systems are adenosine triphosphate (ATP) regulated mechanisms conserved from bacteria to man namely heat shock proteins, Hsp60, Hsp70, Hsp90 and Hsp100. These chaperone classes differ dramatically in sequence and structure, which is highlighted by their different functions [3].

The heat shock protein 90 (Hsp90) family is of particular interest because some of its members are especially dedicated to signal transduction. Hsp90 clients include many of the cancer-related proteins necessary for tumor development, including receptor tyrosine kinases, signal transducers, cell-cycle regulators, and transcriptional factors. Hsp90 is reported to be specifically overexpressed and to exist as activated multi-chaperone complexes in cancer cells and cancer tissues. Some authors have used the word “addiction” to highlight the preference of the cancer cells of Hsp90 for their survival and proliferation.

In human cells there are four Hsp90 isoforms: the heat shock inducible Hsp90α and the constitutively expressed Hsp90β both in the cytosol, mitochondrial Trap1 and Grp94 located in the endoplasmic reticulum (ER).

Hsp90β is one of the most abundant proteins in the human cytosol, it makes up 1-2% of cytosolic protein. Hsp90 can suppress protein aggregation in vitro, independent of ATP. In vivo, however, ATPase activity is essential for the Hsp90 working cycle hence cell viability. Mutant Hsp90s with either faster or slower ATPase rate result in temperature-sensitive growth phenotypes and they are unable to fully activate their client proteins.

Heat Shock Protein 90 (HSP90) has therefore emerged as an attractive target for cancer interventions, and many HSP90 inhibitors have been developed.

Mechanism of Action in TAS-116:

TAS-116 is an orally available, small-molecule and specific heat shock protein α and β (HSP90 α and β) inhibitor. It showed negligible affinity for other two isoforms namely GRP4 and TRAP1. TAS-116 was discovered during a multi-parameter lead optimization campaign to have high target-selectivity for certain HSP90 proteins.

TAS-116 inhibited geldanamycin-FITC binding to HSP90 proteins with K_i values of 34.7 nM, 21.3 nM, greater than 50 uM, and greater than 50 uM for HSP90α  and  HSP90β, GRP94, and TRAP1, respectively. Furthermore, TAS-116 did not inhibit other ATP-ases such as HSP70 (IC₅₀, more than 200 uM) or any of 48 different protein kinases tested (IC₅₀, all more than 30 uM).

Dosages and Approvals:

TAS-116 (Tradename: -) is being developed by Taiho Pharmaceutical (a subsidiary of Otsuka Holdings). TAS-116 is under Phase-I trials in patients with solid tumors and Phase-II clinical trials in Gastrointestinal stromal tumours (GST).

Measured Activities for TAS-116: 

K_i (Inhibition of geldanamycin–FITC binding to HSP90α) = 34.7 ± 8.4 nM

K_i (Inhibition of geldanamycin–FITC binding to HSP90β) = 21.3 ± 3.0 nM

K_i (Inhibition of geldanamycin–FITC binding to GRP94) = greater than 50 uM

K_i (Inhibition of geldanamycin–FITC binding to TRAP1) = greater than 50 uM

%Inh (Inhibition of RPS6KB1 Kinase Activity @ 10 uM TAS-116) = 22%

%Inh (Inhibition of CDK2 Kinase Activity @ 10 uM TAS-116) = 10%

%Inh (Inhibition of STK3 Kinase Activity @ 10 uM TAS-116) = 19%

%Inh (Inhibition of SRC Kinase Activity @ 10 uM TAS-116) = 4%

IC₅₀ (HSP90 binding-activity) = 0.10 uM

Summary

Common name: TAS-116; TAS116; TAS 116

Trademarks: -

Molecular Formula: C25H28N8O

CAS Registry Number: 1260533-36-5

CAS Name: 3-ethyl-4-(3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)benzamide

Molecular Weight: 454.53

SMILES:O=C(N)C1=CC=C(N2N=C(C(C)C)C3=C(N4C=C(C5=CN(C)N=C5)N=C4)C=CN=C32)C(CC)=C1

InChI Key: NVVPMZUGELHVMH-UHFFFAOYSA-N

InChI: InChI=1S/C25H26N8O/c1-5-16-10-17(24(26)34)6-7-20(16)33-25-22(23(30-33)15(2)3)21(8-9-27-25)32-13-19(28-14-32)18-11-29-31(4)12-18/h6-15H,5H2,1-4H3,(H2,26,34)

Mechanism of Action: Heat Shock Protein 90 (HSP90) Inhibitor; HSP90 α/β Inhibitor

Activity: Treatment for Tumors; Cancer Drug

Status: Under Phase Trials

Chemical Class: Small molecules; Amide containing; Pyrazolyl compound; Imidazolyl compound; Benzene containing; Azabicyclo compound

Originator: Taiho Pharmaceutical

TAS-116 Synthesis

US20130289072A1: The patent reports series of novel indazole compounds which are capable of inhibiting HSP90 and shows a cytostatic effect on cancer cells. Compound 6 is TAS-116. The patent reports various intermediates and synthetic routes involved. It also reports the activities of the compounds in various HSP90 assays.

Patent also relates to provision of a drug useful for preventing and/or treating, on the basis of an HSP90 inhibitory effect, a disease in which HSP90 participates, in particular, cancer.

Synthesis of TAS-116

Identifications:

1H NMR (Estimated) for TAS-116

Experimental: ¹H-NMR (DMSO-d₆): δ 8.12 (1H, br s), 8.02 (2H, m), 7.94 (1H, s), 7.91 (1H, dd, J = 8.1, 2.7 Hz), 7.73 (2H, d, J = 10.8 Hz), 7.54-7.48 (3H, m), 7.38 (1H, d, J = 8.1 Hz), 7.24 (1H, d, J = 8.1 Hz), 3.86 (3H, s), 2.88 (1H, q, J = 8.1 Hz), 2.50-2.45 (2H, m), 1.11 (6H, d, J = 5.4 Hz), 1.00 (3H, t, J = 8.1 Hz).

Sideeffects: Nothing till date but all preclinical studies report that TAS-116 demonstrates a safer ocular toxicity profile as compared to other HSP90 inhibitors.

Others:

1.  TAS-116 has been shown to have high oral availability in several species without the need for special formulation or prodrug development.

2. Gastrointestinal toxicity is a major clinical adverse event associated with HSP90 inhibitors. TAS-116 did not inhibit the interaction between GRP94 and LRP6. It is conceivable that a selective inhibitor such as TAS-116 may not cause GRP94-related gastrointestinal toxicity.

3. TAS-116 has strong antitumor activity against several xenografted tumors indicating that inhibition of the HSP90 α and β members of the HSP90 family is sufficient to exert antitumor activity.

4. TAS-116 did not inhibit CYP450 within the effective concentration range, indicating a low drug–drug interaction potential that might allow combination administration with other drugs.

References:

1. Ohkubo, S.; et. al. TAS-116, a highly selective inhibitor of heat shock protein 90a and ß, demonstrates potent antitumor activity and minimal ocular toxicity in preclinical models. Mol Cancer Ther  2015, 14(1), 14 - 22. (free article)

2. Suzuki, R.; et. al. Anti-tumor activities of selective HSP90a/ß inhibitor, TAS-116, in combination with bortezomib in multiple myeloma. Leukemia. 2015, 29(2), 510 - 514. (free article)

3. Advances in Cancer Research, Vol 29. (FMO)

4. Kitade, M.; et. al. Novel indole or indazole derivative or salt thereof. US20130289072A1

1 2 3

Drugs in Clinical Pipeline: AZD5718 | 5-Lipoxygenase Activating Protein (FLAP) Inhibitor | Treatment of Cardiovascular Disorders

AZD5178 is an orally available small molecule inhibitor of 5-lipoxygenase activating protein (FLAP) for the treatment of inflammatory diseases. In a 2016 publication, researchers have disclosed novel pyrazoles that inhibit 5 -lipoxygenase activating protein (FLAP) and therefore leukotriene production. The publication further reports the utility of such pyrazoles in treating and/or preventing clinical conditions including cardiovascular diseases (CVD), such as atherosclerosis, coronary artery disease (CAD), coronary heart disease (CHD), heart failure (HF), high risk coronary artery disease (HRCAD), and abdominal aortic aneurysms (AAA). Also, methods for their therapeutic use, to pharmaceutical compositions containing them and to processes for preparing such compounds are disclosed.

Drugs in Clinical Pipeline: LY3041658 | Treatment of Skin Diseases | Monoclonal Antibody | Chemokine (CXC) Antagonist

LY3041658 is (expected to be a) monoclonal antibody that targets and specifically bind seven human ELR+ CXC chemokines. Such antibodies are useful for treating various inflammatory/autoimmune diseases, such as inflammatory bowel disease (IBD), plaque psoriasis, and palmoplantar pustulosis; and cancer, such as renal cancer or ovarian cancer.

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)

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