Fluorinated APIs

Fluorinated APIs

Introduction

Fluorinated active pharmaceutical ingredient (APIs) are active ingredients of drugs containing one or more fluorine atoms, which is fluorinated compound. Usually, APIs can be either synthetic or naturally extracted. However, because naturally occurring fluorinated compounds are rare, fluorinated APIs are almost exclusively synthetic. Because of high ionization potential, electron affinity and electronegativity, fluorine is a highly electron-absorbing substituent. In addition, fluorocarbon bonds are much stronger than carbon-hydrogen bonds. Thus, fluorinated APIs have a variety of pharmacodynamic and pharmacokinetic properties, such as enhanced binding interactions, metabolic stability, changes in physical properties and selective reactivity, which have become a research hotspot in the field of medicine. At present, a large number of fluorinated APIs have been approved or are in clinical development.

List of Representative Fluorinated APIs

A list of representative fluorinated APIs that either were approved after 2011 by the corresponding agencies or still are in clinical development is shown in below ^[1]. These compounds cover a large number of therapeutic areas, and on this occasion, they are classified according to the number of fluorine atoms or fluorinated moieties.

Classification	Name	Description
Compounds containing one fluorine atom	Afatinib	Afatinib was developed for the potential treatment of non-small-cell lung cancer and other solid tumors.
	Trametinib	Tametinib was developed for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E/K mutations.
	Olaparib	Olaparib was discovered for the potential treatment of BRCA-mutated ovarian and breast cancer as a monotherapy, as well as other tumors such as gastric, prostate, and non-small-cell lung cancer.
	Cabozantinib	Cabozantinib, as a multitargeted tyrosine kinase (such as MET, VEGFR2, RET, Kit, and Flt3) inhibitor, was developed for the oral treatment of metastatic medullary thyroid cancer (MTC).
	Cediranib	Cediranib, as an orally bioavailable inhibitor of pan-vascular endothelial growth factor (pan-VEGF) receptor tyrosine kinase, was developed for the potential treatment of cancer such as glioblastoma treatment.
Compounds containing two fluorine atoms	Omarigliptin	Omarigliptin is a novel potent, selective, and long-acting dipeptidyl peptidase IV (DPP IV) inhibitor for the potential once-weekly oral treatment of type 2 diabetes mellitus (T2DM).
	Isavuconazole	Isavuconazole, as an inhibitor of sterol 14-α-demethylase involved in the biosynthesis of ergosterol, was developed for the potential treatment of severe invasive and life-threatening fungal infections by disruption of fungal membrane structure and function.
	Dolutegravir	Dolutegravir was approved by the FDA in 2013 as the third integrase inhibitor for HIV treatment.
	Ledipasvir	Ledipasvir is an NS5A inhibitor that has the potential to be of utility in combination with direct acting antiviral agents (DAAs) of complementary mechanism in all-oral therapy for the treatment of hepatitis C virus (HCV) infection.
Compounds containing three fluorine atoms	Dabrafenib	Dabrafenib (trade name: Tafinlar) is a small-molecule oral inhibitor of the mutant kinase BRAF, which had been launched in the United States for unresectable or metastatic melanoma with BRAFV600E mutation as detected.
	Cobimetinib	Cobimetinib is a potent and highly selective allosteric inhibitor of MEK1/2 (biochemical IC50 = 4.2 nmol/L against MEK1) for the oral treatment of solid tumors, including melanoma.
Compounds containing one trifluoromethyl group	Tasquinimod	Tasquinimod is a second-generation oral quinoline-3-carboxamide antiangiogenic agent for the treatment of castration-resistant prostate cancer.
	Buparlisib	Buparlisib was developed for the potential treatment of solid and hematological tumors, including endometrial carcinoma, glioblastoma, prostate cancer, breast cancer, melanoma, and myelofibrosis.
	Enobosarm	Enobosarm was developed for the potential treatment of disorders associated with muscle wasting and osteoporosis.
	Teriflunomide	Teriflunomide is oral immunomodulator for the treatment of relapsing forms of multiple sclerosis.
Compounds containing both trifluoromethyl groups and fluorine atoms	Enzalutamide	Enzalutamide, a novel oral AR signaling competitive antagonist with no agonism activity, was received approval by the FDA in September 2012 indicated for patients with mCRPC who have been previously treated with docetaxel.
	Regorafenib	Regorafenib, as a novel oral multikinase inhibitor, was developed for the potential treatment of metastatic colorectal cancer (CRC).

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Reference

1. Zhou Y., et al. Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas[J]. Chemical reviews, 2016, 116(2): 422-518.