III. DISCOVERY OF NOVEL SELECTIVE PAR4 ANTAGONISTS
3.4 Discovery of Novel, Selective PAR4 Antagonists
3.3.8 Dual PAR1/PAR4 inhibition significantly inhibits thrombin-mediated platelet
1.1.8.3 Two pot procedure to chiral aziridines
In summary, we have developed a three-step, one-pot protocol for the general enantioselective synthesis of terminal N-alkyl aziridines via organocatalysis.47 Previous approaches to these useful moieties required long multi-step syntheses, had a lack of generality and substrate scope, and required starting materials that were not readily available. This study has led to the development of a powerful extension of the organocatalyzed enantioselective synthesis of α-chloroaldehydes for the general enantioselective synthesis of N-alkyl terminal aziridines in very high yields and ee. This
new methodology provides access to aziridines utilizing aldehydes and primary amines, thousands of which are commercially available.
(Risperdal, Janssen-Cilag); and the proton-pump inhibitor lansoprazole (Prevacid, Novartis).
Figure 1.2.1.1 Examples of pharmaceuticals containing fluorine.
1.2.2 Effects of the Fluorine Substituent
The reasoning behind a fluorine substitution in a molecule is based on the unique characteristics of the fluorine atom, especially its small size and high electronegativity.
The small size of the fluorine atom is a distinctive characteristic; with a van der Waals radius similar to that of hydrogen and oxygen (Table 1.2.2.1), a fluorine atom is a reasonable substitution for a hydrogen atom or hydroxyl group in a bioactive compound with respect to steric requirements at receptor binding sites.50
Fluorine is also the most electronegative element on the periodic table. As a consequence of this electronegativity, fluorine makes a very strong bond with carbon (Table 1.2.1), and it is often introduced into a target compound in order to improve the metabolic stability by blocking sites that are prone to metabolism such as oxidation by cytochrome P450s (CYP450s). As a result of these unique electronic properties, fluorine may modulate the physicochemical properties of a molecule such as acidity and basicity,
1.141 Lansoprazole
(PPI) O
H HO
F
F H
O O O S F
1.139 Fluticasone (Corticosteroid)
1.140 Risperidone (Antipsychotic) O N
NH
O OH
F HO HO
1.138 Atorvastatin (Cholesterol lowering)
N
O N F
N N O
NH N
S O
N O
CF3
lipophilicity, hydrogen bonding ability, and even the overall conformation of the molecule.48,52
Table 1.2.2.1 Physiochemical properties of the carbon-fluorine bond.
1.2.3 Metabolic Stability of Fluorinated Compounds
In order for an orally administered drug to be effective, it must be able to withstand the physiological pH in the stomach long enough to enter the blood stream and be transported in sufficient quantity to the site of action. It must then perform its desired task efficiently and be metabolized at an appropriate rate into non-toxic materials.
Metabolic stability is one of the most crucial factors in determining the bioavailability of a drug molecule. Low metabolic stability due to CYP450-mediated oxidation processes is a common problem in drug discovery. The incorporation of fluorine has been widely used to alter the pharmacokinetic properties of compounds and block metabolically labile sites. Metabolism can be affected by addition of fluorine either directly at or adjacent to
(Schering-Plough), the first generation of the drug produced a complex metabolic mixture in the bile of rats, which proved to be more potent than the drug itself. The primary metabolism pathways were found to be dealkylation of the N-1 and C-4 methoxyphenyl groups, para hydroxylation of the C-3 side chain phenyl group, and benzylic oxidation.
The benzylic (S)-hydroxy group and C-4 hydroxy groups proved to be beneficial and led to an increase in potency. The non-productive metabolism was blocked by incorporation of fluorine at the remaining metabolically labile sites. The result was a second- generation drug which was found to be 400 times more potent and required lower, less frequent dosing due to the improved metabolic stability in vivo (Figure 1.2.3.1).53
Figure 1.2.3.1 Effect of fluorine on drug metabolism.
1.2.4 Acidity and Basicity Effects from Fluorine
As an incredibly electronegative substituent, fluorine has strong effects on the acidity (and basicity) of neighboring functional groups.48-50 For instance, the inductive effects of a single β-fluorine atom are pronounced, lowering the pKa of a linear aliphatic
difluoro substitution lowering the pKa to ~7.3 and a β-CF3 moiety lowering the pKa to
~5.7 (Figure 1.2.4.1).48-50 These changes can also have important consequences pharmacokinetic properties of a drug; quite often, a change in the pKa has a strong effect on the distribution and absorption of a drug in the body.
Figure 1.2.4.1 The effect of fluorine substitution on pKa.
For example, incorporation of fluorine into a series of 3-piperdinylindole compounds synthesized for migraine treatment (5-HT1D antagonists) led to significantly improved pharmacokinetic profiles of the compounds by lowering the pKa of the piperidine nitrogen (Figure 1.2.4.2).54
Figure 1.2.4.2 Effects of pKa values on the bioavailability and receptor binding.
1.2.5 Mitigation of Off-Target Effects
In addition to improving the pharmacokinetic profiles of compounds, the incorporation of fluorine into a drug can also diminish off-target activity. The human ether a-go-go–related gene (hERG) codes for a protein that contributes to the electrical activity of the heart and helps to coordinate the heart's beating. Activity at the hERG ion channel is a major cause of toxicity in many drug molecules. Several drug candidates have failed in clinical trials due to activity at the hERG ion channel. It is estimated that about 25-40% of all lead compounds will show some hERG activity. Drug activity at hERG results in prolonged electrocardiographic QT intervals, which can give rise to long QT syndrome. These episodes may lead to palpitations, fainting, and sudden death due to ventricular fibrillation.55 Due to toxicity from drug-hERG interactions, the Food and Drug Administration (FDA) and the European Medicines Agency now require a thorough screening of new drugs to check for any hERG activity.56
Evidence has linked T-type Ca2+ channels to several CNS disorders, including epilepsy. Piperidine 1.146 was identified as a potent T-type calcium channel inhibitor with good selectivity against hERG and L-type channels. By reducing the basicity of the piperidine nitrogen through the addition of an electron-withdrawing β-fluorine at the 3- position of the piperidine ring, a threefold reduction in hERG activity was observed in addition to a twofold increase in potency (Figure 1.2.5.1).57
Figure 1.2.5.1 Modulation of hERG activity following fluorine substitution.
1.2.6 Sources of Fluorine
Organofluorine compounds are generally formed using prepared or commercially available nucleophilic, electrophilic, and radical fluorine reagents. Some common examples of nucleophilic fluorine reagents include DAST, DFI, and Deoxofluor (Figure 1.2.6.1).
Figure 1.2.6.1 Common nucleophilic fluorine reagents.
Common examples of electrophilic fluorine reagents include Selectfluor, NFSI, N-fluorocamphor sultam, and N-fluoropyridinium salt (Figure 1.2.6.2). Many methods for
the synthesis of enantioenriched organofluoro compounds have been reported.
Enantioselective fluorination is usually accomplished through substrate-controlled, reagent-controlled, or asymmetric catalytic conditions.
Figure 1.2.6.2 Common electrophilic sources of fluorine.
Despite the importance of the β-fluoroamine moiety, there are few synthetic methods in the literature for its preparation.48-50,58 Two common methods, the ring opening of aziridines with nucleophilic fluoride sources59 and the hydrofluorination of olefins,60 deliver β-fluoroamines but lack generality, require starting materials that are not readily available, and/or do not provide access to enantiopure β-fluoroamines (Scheme 1.2.7.1).