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: Perifosine | Orphan Drug | AKT Inhibitor | Treatment for Cancer | Signal Transduction Pathway Inhibitor | Kinase Inhibitor

Perifosine [1,1-Dimethylpiperidinium-4-yl octadecyl phosphate] is a synthetic oral alkylphospholipid (APL) bearing a piperidine head group. APLs were shown to have selectivity for neoplastic versus normal hematologic cells in vitro. 

Perifosine is an oral Akt inhibitor which unlike most kinase inhibitors that target the adenosine triphosphate (ATP)-binding region, prefers binding to the Pleckstrin Homology (PH) domain of Akt, thereby preventing Akt's translocation to the plasma membrane. It also modulates a number of other key signal transduction pathways, including the JNK and MAPK pathways, all of which are pathways associated with programmed cell death, cell growth, cell differentiation and cell survival. The effects of Perifosine on Akt are of particular interest because of the importance of this pathway in the development of most cancers, with evidence that it is often activated in tumors that are resistant to other forms of anticancer therapy, and the difficulty encountered thus far in the discovery of drugs that will inhibit this pathway without causing excessive toxicity [1, 2].

Perifosine : 2D and 3D Structure

Perifosine is based on the structure of lysophosphatidylcholine and belongs to lysolecithin analogues class of antitumor APLs that also includes Edelfosine and Miltefosine.

Drugs in Clinical Pipeline: LY2603618 | Kinase Inhibitors | Checkpoint Kinase 1 (CHK1) Inhibitor | Cancer Drug

LY2603618 [(R)-1-(5-bromo-4-methyl-2-(2-(morpholin-2-yl)ethyl)phenyl)-3-(5-methylpyrazin-2-yl)urea] is a potent and selective small molecule inhibitor of Checkpoint Kinase 1 (CHK1) protein kinase activity in vitro (IC₅₀ = 7 nM). Moreover, it shows no significant activity towards CHK2 (IC₅₀ = 12000 nM). LY2603618 showed an IC₅₀ value greater than 20 uM for a large number of kinases in a selectivity profiling assay.

It carries the distinction of being the first selective CHK1 inhibitor to enter clinical cancer trials.

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Drugs in Clinical Pipeline: GDC-0425 | Kinase Inhibitors | Checkpoint Kinase (CHK1) Inhibitor | Cancer Drug

GDC-0425 [5-((1-ethylpiperidin-4-yl)oxy)-9H-pyrrolo[2,3-b:5,4-c']dipyridine-6-carbonitrile] is an orally bio-available small molecule inhibitor of checkpoint kinase 1 (CHK1) that has been developed as a treatment for various cancerous malignancies. Chemically, it is a 6-cyano bearing 1,7-diazacarbazole derivative, which resulted from optimization of a 2-aminoazine series for  CHK1 activity.

GDC-0425: 2D and 3D Structure

The oral CHK1 inhibitors GDC-0425 and GDC-0575 have been reported in phase I clinical trials. They have clear advantage on other CHK1 inhibitors in clinical trials that are intravenous agents and have relatively low selectivity for CHK1.

Checkpoint Kinases (CHK) as Drug Targets

Individual cells replicate by making an exact copy of their chromosomes, and then segregating these into separate cells. This cycle of DNA replication, chromosome separation and division is regulated by mechanisms within the cell that maintain the order of the steps and ensure that each step is precisely carried out. Involved in these processes are the cell cycle checkpoints where cells may arrest to ensure DNA repair mechanisms have time to operate prior to continuing through the cycle into mitosis. There are two such checkpoints in the cell cycle-the G1/S checkpoint that is regulated by p53 and the G2/M checkpoint that is monitored by the serine/threonine kinase Checkpoint kinase 1 (CHK1).

CHK1 and CHK2 are structurally unrelated yet functionally overlapping serine/threonine kinases activated in response to genotoxic stimuli. CHK1 and CHK2 relay the checkpoint signals from the Ataxia telangiectasia mutated (ATM) and Ataxia telangiectasia and RAD3-related (ATR), which phosphorylate and activate them.

CHK2 is a stable protein expressed throughout the cell cycle, activated mainly by ATM in response to double-strand DNA breaks (DSBs). In contrast, CHK1 protein expression is largely restricted to S and G2 phases. In response to DNA damage, CHK1 is phosphorylated and activated by ATM/ATR, resulting in cell cycle arrest in the S and G2/M phases to allow for repair of DNA damage.

Inhibition of CHK1 has been shown to abrogate cell cycle arrest leading to enhanced tumor cell death following DNA damage by a range of chemotherapeutics. Cells lacking intact G1 checkpoints are particularly dependent on S and G2/M checkpoints and are therefore expected to be more sensitive to chemotherapeutic treatment in the presence of a CHK1 inhibitor, whereas normal cells with functional G1 checkpoints would be predicted to undergo less cell death. Depending upon the timing of DNA damage, CHK1 will arrest the cell in either the S or G2-phase. These arrest points are called DNA damage checkpoints.

In the presence of single-stranded DNA breaks or stalled replication forks, CHK1 is activated resulting in cell cycle arrest, stabilization of replication origins and suppression of apoptosis. This response acts rapidly to temporarily stall the cell cycle to allow the time necessary to repair DNA damage prior to mitosis. Parallel activation of p53 maintains the G2/M arrest over an extended period of time. In tumor cells with dysfunctional p53, CHK1 becomes the primary mediator of DNA damage-dependent cell cycle arrest. Since p53 signaling is impaired in the majority of human cancers, CHK1 represents a vulnerable pathway target to increase the effectiveness of DNA damaging chemotherapy.

CHK1 is also an important regulator of replication origin firing. In normal cells, CHK1 stabilizes active replication forks and prevents the activation of late stage origins until near the end of S-phase. When CHK1 activity is diminished the number of active replication origins in the cell increases paradoxically resulting in stalled replication forks and an increase in the duration of S-phase.

Mechanism of Action in GDC-0425:

GDC-0425 is reported as an oral and selective small molecule inhibitor of Checkpoint kinase 1 (CHK1). CHK1 inhibition converts a transient genotoxic insult from chemotherapy into a cytotoxic event by overriding cell cycle arrest, allowing cells mitosis with DNA damage.

In a reported study GDC-0425 enhanced gemcitabine (gem) efficacy in tumor xenograft models. Greater chemopotentiation was observed in cancer cell lines lacking p53 activity.

Dosages and Approvals:

GDC-0425 (Tradename: -) is a product that originated and developed by Genetech. In August 2011, Array BioPharma announced an oncology agreement with Genentech, for the development of each company's small-molecule Checkpoint kinase 1 (CHK1) program. The programs include Genentech's compound GDC-0425 (also known as RG7602), currently in Phase I/II, and Array's compound ARRY-575, which is being prepared for an investigational new drug application to initiate a Phase 1 trial in cancer patients.

Under the terms of the agreement, Genentech is responsible for all clinical development and commercialization activities.

Reported Activities for GDC-0425:

GDC-0425 is reported as a selective and specific inhibitor of Checkpoint kinase 1 (CHK1). It is reported to have a better selectivity profile as compared to its competition under Phase trials.

Summary

Common name: GDC-0425; GDC0425; GDC 0425; RG-7602; RG7602; RG 7602

Trademarks: -

Molecular Formula: C18H19N5O

CAS Registry Number: 1200129-48-1

CAS Name: 5-((1-ethylpiperidin-4-yl)oxy)-9H-pyrrolo[2,3-b:5,4-c']dipyridine-6-carbonitrile

Molecular Weight: 321.38

SMILES: CCN(CC1)CCC1OC2=C3C(NC4=C3C=CC=N4)=CN=C2C#N

InChI Key: XEZLBMHDUXSICI-UHFFFAOYSA-N

InChI: InChI=1S/C18H19N5O/c1-2-23-8-5-12(6-9-23)24-17-14(10-19)21-11-15-16(17)13-4-3-7-20-18(13)22-15/h3-4,7,11-12H,2,5-6,8-9H2,1H3,(H,20,22)

Mechanism of Action: Checkpoint Kinase 1 (CHK1) Inhibitors; Kinase Inhibitors

Activity: Antineoplastics; Cancer Drug

Status: Under Phase Trials

Chemical Class: Small molecules; Piperidine containing; 1,7-diazacarbazole derivatives; Nitrile containing; Cyano containing; Ether containing; N-substituted alkyl derivatives

Originator: Genetech Pharma / Array Biopharma

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Sideeffects:

In a Phase I trial combination therapy trials of GDC-0425 and Gemcitabine, patients received GDC-0425 alone for a 1-week lead-in followed by 21-day cycles of gemcitabine plus GDC-0425. The maximum tolerated dosage (MTD) of GDC-0425 was 60 mg when administered approximately 24 hours after gemcitabine 1000 mg/m². Gemcitabine was initiated as 750 mg/m² (Arm A), then increased to 1000 mg/m² (Arm B).

The most common treatment related adverse events (TEAEs) were nausea; anemia, neutropenia, vomiting; fatigue; pyrexia; and thrombocytopenia. Moreover, the participants had increased Alanine Aminotransferases (ALTs) readings.

Others:

Coming up.

References:

Coming up.

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Drugs in Clinical Pipeline: TGR-1202 | Orphan Drug | Kinase Inhibitor | Phosphoinositide 3-kinase delta (PI3Kδ) Inhibitors | Cancer Drug

TGR-1202 [(S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one] is a potent, orally available, small molecule selective phosphoinositide 3-kinase (PI3K) delta (PI3Kδ;  IC₅₀ = 22.23 nM) kinase inhibitor with high selectivity over all other PI3K isoforms (48 – 10000 times) as well that for a 441-kinase panel. The selectivity and activity of TGR-1202 is credited to its design with a unique backbone compared to other PI3K inhibitors in development [1, 2].

TGR-1202 : 2D and 3D Structure

TGR-1202 is currently under clinical development for patients with relapsed and refractory hematological malignancies.

On Aug 24, 2016 TG Therapeutics, Inc. announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for the oral, next generation PI3K-delta (PI3Kδ) inhibitor, TGR-1202, in the treatment of patients with Chronic Lymphocytic Leukemia (CLL).

Ripasudil | Kinase Inhibitor | ROCK Inhibitor | Treatment of Glaucoma | Treatment of Ocular Hypertension

Ripasudil [(S)-4-Fluoro-5-[(2-methyl-1,4-diazepan-1-yl)sulfonyl]isoquinoline] is a small molecule, highly potent and selective Rho-associated coiled coil-containing protein (ROCK) kinase inhibitor having the (S)-2-methyl-1,4-diazepane moiety. It was developed as promising candidate for the treatment of ocular hypertension with intraocular pressure-lowering activity and neuroprotection of retinal ganglion cells injured in glaucoma. The S configuration at the 2-position on the 1,4-diazepane ring of Ripasudil plays the pivotal role for expressing the physiological feature [1].

Ripasudil: 2D and 3D Structure

Ripasudil has been developed from Fasudil. Both compounds have the same core structure of 5-(1,4-diazepan-1-ylsulfonyl)isoquinoline. Fasudil has been recognized as a potent Rho-kinase inhibitor and clinically used for the treatment of cerebral vasospasm. After exploring the chemical derivatives of Fasudil, the incorporation of fluorine atom at C4 position of isoquinoline moiety and the chiral attachment of the methyl group at C2’ position of 1,4-diazepane moiety dramatically improved the pharmacological action. Ripasudil showed much more potent and selective Rho-kinase inhibitory activity than Fasudil and would be potentially expected to cure the Cerebral Vascular Disorder. Especially, it is noteworthy that Ripasudil is effective on the ocular hypertension with intraocular pressure (IOP)-lowering activity and neuroprotection of retinal ganglion cells injured in glaucoma. 

A 0.4% ophthalmic solution of Ripasudil was approved in Japan in September 2014 for the treatment of glaucoma and ocular hypertension when other therapeutic drugs are not effective or cannot be administered, at a dosage of 1 drop in the eye, twice daily.

Glaucoma and ROCK Inhibitors

Glaucoma is a disease that primarily damages the optic nerve head, which causes characteristic visual field loss and can eventually lead to blindness. The disease can be divided into two broad categories, open-angle and angle-closure (closed-angle) glaucoma, based on the appearance of the anterior chamber angle. The most common form of the disease is primary open-angle glaucoma (POAG), and chronically elevated intraocular pressure (IOP) occurs as a result of pathologically increased resistance to the drainage of aqueous humor through the outflow pathways.

The level of IOP is a risk factor for progression not only in POAG patients but also in normal tension glaucoma (NTG) patients, and it is therefore very important to reduce the IOP for glaucoma therapy.

Currently, available anti-glaucoma drugs are classified into two types-the first type decreases aqueous humor production and includes β-adrenergic blockers and carbonic anhydrase inhibitors, while the second class enhances uveoscleral outflow and includes prostaglandin analogs.

The trabecular meshwork, which is located in the anterior chamber angle, is responsible for draining the aqueous humor from the anterior chamber for conventional outflow, and is an ideal target for the effective management of IOP in patients. ROCK (Rho-associated coiled coil-containing protein kinase) is a serine/threonine kinase that serves as an important downstream effector of Rho GTPase, and plays a critical role in regulating the contractile tone of smooth muscle tissues in a calcium independent manner. ROCK has two isoforms (ROCK1 and ROCK2), both of which are expressed in the human trabecular meshwork and ciliary muscle cells.

Ripasudil as Kinase Inhibitor

Ripasudil showed potent and selective inhibitory effects on ROCKs. The 50% inhibitory concentration (IC₅₀) of Ripasudil for ROCK 2 (0.019 uM) was 2.68 times lower (higher inhibitory effect) than that for ROCK 1 (0.051 uM). In addition, the IC₅₀s of Ripasudil for PKACα, PKC, and CaMKIIα (2.1, 2.7 and 0.37 uM) were 111, 1420, and 19.5 times higher than that for ROCK 2, respectively [1].

Summary

Common name: K 115; K-115; K115; Ripasudil hydrochloride hydrate

Trademarks: Glanatec

Molecular Formula: C15H18FN3O2S

CAS Registry Number: 223645-67-8; 887375-67-9 (HCl Dihydrate)

CAS Name: 4-fluoro-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline

Molecular Weight: 323.39

SMILES: O=S(=O)(c2c1c(F)cncc1ccc2)N3[C@H](CNCCC3)C

InChI Key: QSKQVZWVLOIIEV-NSHDSACASA-N

InChI: InChI=1S/C15H18FN3O2S/c1-11-8-17-6-3-7-19(11)22(20,21)14-5-2-4-12-9-18-10-13(16)15(12)14/h2,4-5,9-11,17H,3,6-8H2,1H3/t11-/m0/s1

Mechanism of Action: Rho-associated kinase inhibitor; Kinase Inhibitor; ROCK Inhibitor

Activity: Treatment of Glaucoma; Treatment of Ocular Hypertension; Antineovascularisation Agents; Antiglaucoma Preparations and Miotics

Status: Launched 2014 (Japan)

Chemical Class: Azepines; Isoquinolines; Small-Molecules; Sulphonamides; Fluorine containing

Originator: Kowa Company, Ltd/D. Western Therapeutics Institute, Inc.

Ripasudil Synthesis

WO2012026529A1: The patent reports multi-kilogram synthesis of Ripasudil. 

Intermediate:

Final Synthesis:

Identifications:

Experimental: ¹H-NMR (DMSO-d₆) δ: 1.20 (3H, d, J = 6.6 Hz), 1.98-2.07 (2H, m), 3.06-3.16 (1H, m), 3.22-3.31 (2H, m), 3.35 (4H, s), 3.44 (1H, dd, J = 14.1, 4.4 Hz), 3.59-3.74 (2H, m), 4.37-4.47 (1H, m), 7.93 (1H, t, J = 7.8 Hz), 8.32 (1H, d, J = 7.8 Hz), 8.54-8.60 (1H, m), 8.72 (1H, d, J = 4.9 Hz), 9.39 (1H, s), 9.51 (2H, br s).

Experimental: ¹³C-NMR (DMSO-d₆) δ: 16.6, 26.8, 42.9, 45.5, 50.3, 50.9, 120.9 (J = 12.4 Hz), 127.5, 130.7 (J = 1.7 Hz), 132.2, 132.5 (J = 27.3 Hz), 133.2 (J = 5.0 Hz), 133.3, 149.8 (J = 5.0 Hz), 152.0 (J = 264.0 Hz).

References:
1. Isobe, T.; et. al. Effects of K-115, a rho-kinase inhibitor, on aqueous humor dynamics in rabbits. Curr Eye Res 2014, 39(8), 813-822. (FMO only)
2. Noriaki, G.; et. al. Novel process for the preparation of isoquinoline derivatives or salts thereof. WO2012026529A1

Osimertinib | Mutant Selective EGFR Inhibitor | Kinase Inhibitor | Orphan Drug | Treatment for NSCLC

Osimertinib [N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide] is an oral, small molecule, irreversible and mutant-selective inhibitor of epidermal growth factor receptor (EGFR) kinase activity. Chemically, Osimertinib is a mono-anilino-pyrimidine compound that is structurally and pharmacologically distinct from all other third-generation tyrosine kinase inhibitors (TKIs) including CO-1686 and WZ4002 [1, 2].

Osimertinib: 2D and 3D Structure

Osimertinib is designed in such a manner that it irreversibly and selectively targets both sensitizing and resistant-T790M mutant EGFR whilst harboring less activity towards wild-type EGFR. Osimertinib has been developed to target the EGFR T790M mutation that is often present in NSCLC patients with acquired EGFR TKI resistance, while sparing wild-type EGFR. 

Osimertinib was granted US FDA breakthrough therapy designation, orphan drug status and fast track status for non-small cell lung cancer (NSCLC) in 2014, and was granted US FDA priority review designation by early September 2015. In May 2015, Osimertinib was granted accelerated assessment status in the same indication in the EU, and received priority review status in Japan in the third quarter of 2015. 

Osimertinib has been designed to target the EGFR T790M mutation that is often present in NSCLC patients with acquired EGFR TKI resistance, while sparing wild-type EGFR. In November 2015, the tablet formulation of osimertinib was granted accelerated approval in the USA for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on or after EGFR TKI therapy [1].

Dosages and Approvals:

In Nov 2015, Osimertinib (Tradename: Tagrisso) a third-generation EGFR TKI that targets tumours with certain EGFR mutations, including T790M,got an  accelerated approval from the US FDA for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC (as detected by an FDA-approved test) who have progressed on or after EGFR TKI therapy.

The recommended dosage of Osimertinib is 80 mg once daily until unacceptable toxicity or disease progression (PD). Osimertinib tablets (available as 40 and 80 mg) can be taken with or without food, or in patients who have difficulty swallowing solids, dispersed in about 50 mL of noncarbonated water and immediately consumed or administered via nasogastric tube. 

A joint effort of AstraZeneca and University of Cambridge since 2014 is credited with discovery of Osimertinib, where the university’s researchers gain access to key compounds from AstraZeneca’s investigation pipeline, including Osimertinib. In October 2015, AstraZeneca entered into a collaborative agreement with Eli Lilly to investigate the use of Osimertinib as combination therapy (with Ramucirumab or Necitumumab) in patients with solid tumours.

Osimertinib Synthesis

J Med Chem 2014, 57(20), 8249-8267: It is one of the earliest reported synthetic route for Osimertinib. The article details the design, discovery and activity of Osimertinib and its various analogues.

Starting Material (Route 1):

Route 2: Shorter with better yields too !!!

 

Final Synthesis:

Identifications:

1H NMR (Estimated) for Osimertinib

Experimental: ¹H NMR (400 MHz, DMSO, 22 °C) δ 2.21 (6H, s), 2.29 (2H, t), 2.72 (3H, s), 2.89 (2H, t), 3.86 (3H, s), 3.92 (3H, s), 5.77 (1H, dd), 6.27 (1H, dd), 6.43 (1H, dd), 7.04 (1H, s), 7.15 (1H, t), 7.2-7.27 (2H, m), 7.53 (1H, d), 7.91 (1H, s), 8.24 (1H, d), 8.33 (1H, d), 8.68 (1H, s), 9.14 (1H, s), 10.22 (1H, s).

13C-NMR (Estimated) for Osimertinib

Experimental: ¹³C NMR (176 MHz, DMSO, 22 °C) δ 32.8, 42.6, 45.1, 55.7, 56.0, 56.8, 105.3, 107.1, 110.4, 112.4, 113.3, 120.8, 121.2, 121.9, 125.3, 125.5, 125.9, 127.7, 132.4, 133.8, 137.3, 137.7, 145.8, 157.6, 158.9, 159.8, 161.5, 162.3.

Sideeffects: The most common adverse events (AEs) of any grade with Osimertinib (occurring with greater than 20 % incidence) were diarrhea (47 %), rashes and acne (group term; 40 %), nausea (22 %), decreased appetite (21 %) and dry skin (20 %). The incidences of some adverse events, including diarrhoea and rash, increased in a dose-dependent fashion.

Based on clinical trial data, the US prescribing information for Osimertinib carries warnings and precautions regarding the increased risk of ILD/pneumonitis, QTc interval prolongation and cardiomyopathy during treatment.

Results from clinical trials reveal that pneumonitis-like events were reported in six patients (2.4 %), all of whom stopped treatment and had resolved or were resolving at the time of analysis. Eleven patients (4.3 %) experienced prolongation of QTc interval and six patients (2.4 %) reported hyperglycaemia during Osimertinib treatment; none of these patients required dosage reduction or drug discontinuation. Of the seven fatal adverse events with Osimertinib, one case of pneumonia was considered to be possibly treatment-related.

References:
1. Greig, S. L. Osimertinib: First Global Approval. Drugs 2016, 76(2), 263-73. (FMO only)
2. Finlay, M. R.; et. al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem 2014, 57(20), 8249-67. (FMO only)

Apatinib | Kinase Inhibitor | VEGFR-2 Inhibitor | KDR Inhibitor | Angiogenesis Inhibitor | Anti-Tumor Drug

Apatinib [N-[4-(1-cyano-cyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridine carboxamide] is an orally available, selective small molecule inhibitor of vascular endothelial growth factor-2 (VEGFR-2 also known as KDR) tyrosine kinase. It is more potent than Sunitinib in inhibiting VEGFR2 (IC₅₀ Apatinib, Sunitinib = 0.001, 0.005 uM) [1, 2].

Apatinib is an analogue of Valatinib and shows similar anti-angiogenic/anti-tumour efficacy. It binds with VEGFR-2 tyrosine kinase targeting the intracellular ATP binding site of the receptor, preventing phosphorylation and subsequent downstream signalling. Apatinib has shown a superior in vivo efficacy compared to Valatinib in xenograft models.

Apatinib has been approved by the Chinese Food and Drug Administration (CFDA) in October 2014 for the treatment of metastatic gastric carcinoma. It is an investigational cancer drug in many other countries including USA, EU etc and currently undergoing clinical trials as a potential targeted treatment for metastatic gastric carcinoma, metastatic breast cancer and advanced hepatocellular carcinoma.

Apatinib: 2D and 3D Structure

Angiogenesis, Tumor Angiogenesis and VEGFRs

Angiogenesis, the formation of new blood vessels from pre-existing ones, plays a central role in the process of tumor growth and metastasis. The proliferation of endothelium and formation of new blood vessels further the size of solid tumors. It is expected that blocking angiogenesis will be an efficient therapeutic approach against many tumor types.

Tumor angiogenesis plays a critical role in the malignant tumor growth and metastasis. When tumors grow beyond 1 mm³, angiogenesis or generation of vascular arborizations by budding from existing vessels is necessary to provide enough blood for the survival of tumor cells. The growth speed and tendency of metastasis of tumors are associated with the level of neovascularization factors and the quantity of nascent microvessels. Since the hypothesis “anti-angiogenesis therapy” was put forward by Folkman in early 1970s, people have made considerable progress in this field, and inhibiting angiogenesis of tumors has been universally accepted as a new anticancer strategy. 

Tyrosine kinase vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play significantly important roles in angiogenesis of tumors, and they are both important targets in blocking angiogenesis of tumors. Vascular endothelial growth factor (VEGF) is the foremost factor in vivo promoting the angiogenesis. The binding of VEGF with vascular endothelial growth factor receptor (VEGFR) in endothelial cells leads to various reactions of angiogenesis, such as cells proliferation, cells metastasis, the increase of vascular permeability, and the move of endothelial cells precursors out of marrow. VEGFR family comprises VEGFR1 (Flt-1), VEGFR2 (KDR/Flk-1) and VEGFR3 (Flt-4). Promotion of the angiogenesis is mainly mediated by the bonded VEGF and VEGFR2 (KDR/Flk-1).

Compared with traditional cytotoxic drugs which inhibit the growth of tumors, angiogenesis targeting drugs are more specific and less toxic as well as helpful to overcome the drug resistance of tumors and can be used for the treatment of various tumors [3, 4].

Apatinib as Kinase Inhibitor

In vitro enzyme experiments showed that Apatinib was an even more selective inhibitor of VEGFR-2 than Sunitinib, with an IC₅₀ of 0.001 uM and 0.005 uM, respectively. Apatinib could also potently suppress the activities of Ret, c-Kit and c-Src with an IC₅₀ of 0.013 uM, 0.429 uM and 0.53 uM, respectively. Apatinib had no significant effects on EGFR, Her-2 or FGFR1 in concentrations up to 10 uM [1].

Summary

Common name: YN968D1; YN 968D1; YN-968D1

Trademarks: -

Molecular Formula: C24H23N5O

CAS Registry Number: 811803-05-1; 1218779-75-9 (mesylate)

CAS Name: N-[4-(1-cyano-cyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridine carboxamide

Molecular Weight: 397.48

SMILES:O=C(NC1=CC=C(C2(C#N)CCCC2)C=C1)C3=CC=CN=C3NCC4=CC=NC=C4

InChI Key: WPEWQEMJFLWMLV-UHFFFAOYSA-N

InChI: InChI=1S/C24H23N5O/c25-17-24(11-1-2-12-24)19-5-7-20(8-6-19)29-23(30)21-4-3-13-27-22(21)28-16-18-9-14-26-15-10-18/h3-10,13-15H,1-2,11-12,16H2,(H,27,28)(H,29,30)

Mechanism of Action: Kinase Inhibitor; KDR Inhibitor; Multi-Kinase Inhibitor

Activity: Treatment of Metastatic Gastric Carcinoma; Anti-cancer Agents; Angiogenesis Inhibitors

Status: Launched 2014 (China)

Chemical Class: Small-molecules; Nitrile containing; Pyrimidine containing

Originator: Advenchen Laboratories (USA)/ Jiangsu Hengrui Medicine Co. Ltd (China)

Apatinib Synthesis

US20040259916A1: It appears to be the industrial process.

Identification:

1H NMR (Estimated) for Apatinib

References:
1. Tian, S.; et al. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci 2011, 102(7), 1374-80. (FMO only)
2. Chen, G. Six membered amino-amide derivatives an angiogenisis inhibitors. US20040259916A1
3. Yuan, K.; et al. The salts of n-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridyl methyl)amino-3-pyridinecarboxamide. WO2010031266A1
4. Sharma, P. S.; et al. VEGF/VEGFR pathway inhibitors as anti-angiogenic agents: present and future. Curr Cancer Drug Targets 2011, 11(5), 624-53. (FMO only)