New Approved Drugs Appearing in the Pharmaceutical Market in 2022 Featuring Fragments of Tailor-Made Amino Acids and Fluorine

The strategic fluorination of oxidatively vulnerable sites in bioactive compounds is a relatively recent, widely used approach allowing us to modulate the stability, bio-absorption, and overall efficiency of pharmaceutical drugs. On the other hand, natural and tailor-made amino acids are traditionally used as basic scaffolds for the development of bioactive molecules. The main goal of this review article is to emphasize these general trends featured in recently approved pharmaceutical drugs.


Introduction
Modern pharmaceutical drugs feature tremendous molecular variety in terms of size, shape, and chemical functionalities. Nevertheless, thorough structural analysis allows us to find two clear similarities: a framework derived from a parent amino acid (AA), and the presence of fluorine [1,2]. Being ubiquitous naturally occurring compounds, AAs have traditionally played an important role in areas of life sciences, such as the development of new pharmaceuticals, medicinal formulations, biosensors, and drug delivery systems [3][4][5][6][7][8][9][10]. Indeed, in the modern paradigms of medicinal chemistry and drug discovery, tailor-made AAs [11] are indispensable components increasingly found in newly marketed pharmaceutical products [12][13][14][15][16][17][18]. Thus, over 30% of small-molecule drugs contain residues of tailor-made AAs or amino-alcohols and di-amines derived from them [12][13][14][15][16][17][18]. In contrast to AAs, the building blocks of life, fluorine is essentially a xenobiotic element [19][20][21], with nearly zero footprint in biochemical evolution. Nevertheless, since the discovery of fludrocortisone in 1953 [22][23][24]-the first Food and Drug Administration (FDA)-approved fluorine-containing drug-the idea of introducing fluorine into biologically active compounds has attracted the close attention of the pharmaceutical industry. Nowadays, over 30% of marketed drugs contain at least one fluorine atom [25][26][27][28][29][30][31][32]. Quite naturally, chemistry practitioners constantly pay very special attention to the records relevant to new pharmaceutical drugs, particular aspects of their structural design, and therapeutic areas. Considering the current role of tailor-made AAs and fluorine in the development of modern drugs, one may agree that the discussion of compounds featuring these two traits might be of keen interest to the appropriate scientific community. The goal of this review article is to profile 10 ( Figures 1 and 2) out of 22 FDA-approved small-molecule drugs, all new tailor-made AA-derived/fluorine-containing drugs introduced to the market in 2022. For each compound, the general mode of biological activity and synthetic routes are presented.

Adagrasib (Krazati TM )
Adagrasib (1, MRTX849; Krazati), a potent and selective KRAS inhibitor of the RAS GTPase family, was developed by Mirati Therapeutics as an anticancer compound to treat non-small cell lung cancer (NSCLC). The molecule specifically targets cysteine 12 residue, the most common KRAS mutation [33], and the compound inhibits the downstream signaling pathway and demonstrates anti-tumor activity. In February 2022, the FDA accepted a new drug application filing for adagrasib (1) for the treatment of patients with previously treated KRASG12C-positive NSCLC. Further, in December 2022, the FDA granted accelerated approval to adagrasib for the treatment of KRASG12C-mutated NSCLC patients who have received at least one prior systemic therapy [34][35][36][37][38][39][40][41].
A series of analogs with tetrahydropyrimidine moieties have been reported in the literature to act as irreversible covalent inhibitors of KRASG12C [35,36]. Compound 11 was reported as an irreversible covalent inhibitor binding cysteine12 in the binding pocket

Adagrasib (Krazati TM )
Adagrasib (1, MRTX849; Krazati), a potent and selective KRAS inhibitor of the RAS GTPase family, was developed by Mirati Therapeutics as an anticancer compound to treat non-small cell lung cancer (NSCLC). The molecule specifically targets cysteine 12 residue, the most common KRAS mutation [33], and the compound inhibits the downstream signaling pathway and demonstrates anti-tumor activity. In February 2022, the FDA accepted a new drug application filing for adagrasib (1) for the treatment of patients with previously treated KRASG12C-positive NSCLC. Further, in December 2022, the FDA granted accelerated approval to adagrasib for the treatment of KRASG12C-mutated NSCLC patients who have received at least one prior systemic therapy [34][35][36][37][38][39][40][41].
A series of analogs with tetrahydropyrimidine moieties have been reported in the literature to act as irreversible covalent inhibitors of KRASG12C [35,36]. Compound 11 was reported as an irreversible covalent inhibitor binding cysteine12 in the binding pocket of KRAS. The pharmacokinetic limitations of 11 led to the development of adagrasib (1) (Figure 3). The rational drug discovery approach to identify the title compound 1 began with the observation that removal of the hydroxyl group from 11 resulted in a fivefold improvement in oral bioavailability. Further, optimization to increase potency was performed after visualizing the crystal structure of the dehydroxy analog complexed to KRASG12C wherein a bound water molecule was complexed to Gly10 and Thr58, and the displacement of this water could lead to an increase in potency. Further optimization led to the 8-chloro analog with an IC 50 value of 1 nM. The title compound 1, having a 2-fluoroacrylamide group, provides increased half-life across species due to a decrease in GSH metabolism while maintaining potency (IC 50 = 5-14 nM).
Molecules 2023, 28, 3651 4 of 21 of KRAS. The pharmacokinetic limitations of 11 led to the development of adagrasib (1) (Figure 3). The rational drug discovery approach to identify the title compound 1 began with the observation that removal of the hydroxyl group from 11 resulted in a fivefold improvement in oral bioavailability. Further, optimization to increase potency was performed after visualizing the crystal structure of the dehydroxy analog complexed to KRASG12C wherein a bound water molecule was complexed to Gly10 and Thr58, and the displacement of this water could lead to an increase in potency. Further optimization led to the 8-chloro analog with an IC50 value of 1 nM. The title compound 1, having a 2-fluoroacrylamide group, provides increased half-life across species due to a decrease in GSH metabolism while maintaining potency (IC50 = 5-14 nM). The synthesis of adagrasib (1) is shown in Scheme 1 [35,36]. The first step is the condensation of the starting material 12 and urea to provide the bicyclic dione core, which is followed by chlorination with POCl3 to provide 13. The Buchwald coupling reaction is employed, wherein the C2 prolinol side chain is attached, followed by benzyl hydrogenolysis to give compound 14. The intermediate 14 is converted to 8-chloronaphthyl substituted intermediate 15, which then undergoes displacement of trifluoromethanesulfonate (OTf) by (S)-2-(piperazin-2-yl)acetonitrile (16) to afford the intermediate 17. Finally, amidation of compound 17 with propylphosphonic anhydride (T3P) as the coupling reagent affords adagrasib (1). The synthesis of adagrasib (1) is shown in Scheme 1 [35,36]. The first step is the condensation of the starting material 12 and urea to provide the bicyclic dione core, which is followed by chlorination with POCl 3 to provide 13. The Buchwald coupling reaction is employed, wherein the C2 prolinol side chain is attached, followed by benzyl hydrogenolysis to give compound 14. The intermediate 14 is converted to 8-chloronaphthyl substituted intermediate 15, which then undergoes displacement of trifluoromethanesulfonate (OTf) by (S)-2-(piperazin-2-yl)acetonitrile (16) to afford the intermediate 17. Finally, amidation of compound 17 with propylphosphonic anhydride (T3P) as the coupling reagent affords adagrasib (1).

Oteseconazole (Vivjoa™)
Oteseconazole (3) is an effective oral antifungal agent developed by Mycovia Pharmaceuticals [58]. It can inhibit cytochrome P450 (CYP51), thus affecting the formation and integrity of fungal cell membranes. The binding strength of oteseconazole to CYP51 is gen-erally similar to that of other azole antifungal agents, including fluconazole, which inhibits CYP51 activity in a manner consistent with tight binding inhibition. However, compared with other azole antibacterial agents, oteseconazole does not show inhibitory activity of human CYP51 [59,60]. Study results have confirmed the effectiveness of oteseconazole in the treatment of the initial episode of vulvovaginal candidiasis (VVC) and strengthened its effectiveness and safety in the treatment of recurrent vulvovaginal candidiasis (RVVC) compared with the current standard-care drug, fluconazole, for VVC [61]. Oteseconazole is a chiral compound that contains a difluoromethyl-pyridine unit, a tetrazole heterocyclic moiety, and a difluorophenyl group at the carbinol center ( Figure 4). Structure-activity relationship (SAR) studies by Viamet Pharmaceuticals Inc. disclosed that the substitution of trifluoroethyl ether by a chloro group led to decreased inhibitory activity against Trichophyton rubrum (T. rubrum) (T. rubrum MIC values of <0.001 and 0.004 for compounds 3 and 28, respectively) [62]. On April 26, 2022, the FDA approved the oral antifungal drug Vivjoa (oteseconazole) to reduce the incidence rate of RVVC in women [58].

Oteseconazole (Vivjoa™)
Oteseconazole (3) is an effective oral antifungal agent developed by Mycovia Pharmaceuticals [58]. It can inhibit cytochrome P450 (CYP51), thus affecting the formation and integrity of fungal cell membranes. The binding strength of oteseconazole to CYP51 is generally similar to that of other azole antifungal agents, including fluconazole, which inhibits CYP51 activity in a manner consistent with tight binding inhibition. However, compared with other azole antibacterial agents, oteseconazole does not show inhibitory activity of human CYP51 [59,60]. Study results have confirmed the effectiveness of oteseconazole in the treatment of the initial episode of vulvovaginal candidiasis (VVC) and strengthened its effectiveness and safety in the treatment of recurrent vulvovaginal candidiasis (RVVC) compared with the current standard-care drug, fluconazole, for VVC [61]. Oteseconazole is a chiral compound that contains a difluoromethyl-pyridine unit, a tetrazole heterocyclic moiety, and a difluorophenyl group at the carbinol center ( Figure  4). Structure-activity relationship (SAR) studies by Viamet Pharmaceuticals Inc. disclosed that the substitution of trifluoroethyl ether by a chloro group led to decreased inhibitory activity against Trichophyton rubrum (T. rubrum) (T. rubrum MIC values of <0.001 and 0.004 for compounds 3 and 28, respectively) [62]. On April 26, 2022, the FDA approved the oral antifungal drug Vivjoa (oteseconazole) to reduce the incidence rate of RVVC in women [58].

Vonoprazan/Amoxicillin/Clarithromycin (Voquezna TM )
Vonoprazan (4) was developed by Takeda Corporation of Japan and approved for the treatment of gastroesophageal reflux disease (GERD) in Japan on 16 December 2014 [64]. Vonoprazan (4) contains a fluorophenyl unit and a pyridin-3-ylsulfonyl pyrrole ring. It is a potassium-competitive acid blocker to inhibit the acid secretion rate of gastric parietal cells [65]. Because vonoprazan (4) has a long half-life and longer action time, it is considered an effective long-term proton pump inhibitor (PPI) [66]. The earliest randomized doubleblind phase III experiment showed that the eradication rate of Helicobacter pylori (Hp) in the population with a vonoprazan protocol was 92.6%, while the eradication rate of Hp in the population with a lansoprazole protocol was 75.9% [67][68][69]. On 3 May 2022, vonoprazan (4) combined with amoxicillin and clarithromycin was approved by the FDA with the trade name Voquezna TM for the treatment of adult Hp infection. These approvals were supported by the results from phase 3 of the phalcon-EE double-blind trial.
The synthesis of vonoprazan (4) is shown in Scheme 4 [70], using the corresponding α-bromoacetophenone derivative as the starting material. The first step is the condensation reaction of 2-bromo-1-

Vonoprazan/Amoxicillin/Clarithromycin (Voquezna TM )
Vonoprazan (4) was developed by Takeda Corporation of Japan and approved for the treatment of gastroesophageal reflux disease (GERD) in Japan on 16 December 2014 [64]. Vonoprazan (4) contains a fluorophenyl unit and a pyridin-3-ylsulfonyl pyrrole ring. It is a potassium-competitive acid blocker to inhibit the acid secretion rate of gastric parietal cells [65]. Because vonoprazan (4) has a long half-life and longer action time, it is considered an effective long-term proton pump inhibitor (PPI) [66]. The earliest randomized double-blind phase III experiment showed that the eradication rate of Helicobacter pylori (Hp) in the population with a vonoprazan protocol was 92.6%, while the eradication rate of Hp in the population with a lansoprazole protocol was 75.9% [67][68][69]. On May 3, 2022, vonoprazan (4) combined with amoxicillin and clarithromycin was approved by the FDA with the trade name Voquezna TM for the treatment of adult Hp infection. These approvals were supported by the results from phase 3 of the phalcon-EE double-blind trial.
The synthesis of vonoprazan (4) is shown in Scheme 4 [70], using the corresponding α-bromoacetophenone derivative as the starting material. The first step is the condensation reaction of 2-bromo-1-    (5), also known as 177 Lu PSMA-617, is a small molecule designed to bind with prostate-specific membrane antigen (PSMA) [71][72][73]. Pluvicto uses high-affinity targeting ligands to guide effective radiotherapy to prostate cancer cells. The specific target of this therapy comes from the "ligand" part of the therapeutic agent. The PSMA-targeted ligand in Pluvicto is chemically connected to a therapeutic radioactive atom called Lutetium-177 ( 177 Lu), which releases high-energy β particles to accurately transmit cytotoxic radiation to the disease site [74]. Different from traditional external radiotherapy, Pluvicto is administered by systemic injection, which could directly target multiple PSMA-positive prostate cancer sites throughout the body, including bones and soft tissues. On March 23, 2022, FDA approved Pluvicto for the treatment of adult patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have received androgen receptor pathway inhibition and taxane-based chemotherapy. These regulatory decisions were supported by the key phase III VISION study results, in which the death risk of PSMA-positive mCRPC patients receiving Pluvicto plus standard treatment was statistically significantly reduced [75]. 177 Lu vipivotide tetraxetan (5)

Mavacamten (Camzyos TM )
Mavacamten (6) is an oral selective allosteric inhibitor of cardiac myosin adenosine triphosphate (ATP) enzyme; it was the world's first innovative therapeutic drug directly targeting the pathophysiological mechanism of hypertrophic cardiomyopathy (HCM) [78][79][80]. It can reduce the contraction force of sarcomeres and reversibly inhibit the coupling reaction between myosin and actin by inhibiting MYH7 mutation, which leads to an increase in myosin ATPase activity. Mavacamten (6) can reduce the sensitivity of the myocardium to Ca 2+ , which may be due to it delaying the formation of the cross bridge and accelerating the separation of the cross bridge, so that the myocardial contractility can return to normal. At the same time, it can also promote the whole myosin group to change into an energy-saving super-relaxation state, and improve diastolic function and energy metabolism [81,82]. On April 28, 2022, mavacamten (6) was approved by the FDA with the name Camzyos TM to treat adults with symptomatic New York Heart Association (NYHA) Class II-III obstructive hypertrophic cardiomyopathy to improve functional ability and symptoms. Camzyos is the first and only FDA-approved allosteric and reversible inhibitor of cardiac myosin, targeting the potential pathophysiology of obstructive HCM [83].

Daridorexant (Quviviq TM )
Daridorexant (7) is a dual orexin receptor (DOR) antagonist, developed by the Swiss biotechnology company Idorsia, that is used to treat adult patients with insomnia. Daridorexant plays a hypnotic role by blocking the binding of neuropeptides orexin A and orexin B with receptors OX1R and OX2R [85,86]. The results of a phase III clinical trial showed that daridorexant significantly improved the total sleep time by comparison with placebo in the first and third months of treatment [87]. Daridorexant (7) received approval from the FDA on 7 January 2022 with the trade name Quviviq [88]. Scheme 6. Synthesis of mavacamten (6).

Daridorexant (Quviviq TM )
Daridorexant (7) is a dual orexin receptor (DOR) antagonist, developed by the Swiss biotechnology company Idorsia, that is used to treat adult patients with insomnia. Daridorexant plays a hypnotic role by blocking the binding of neuropeptides orexin A and orexin B with receptors OX 1 R and OX 2 R [85,86]. The results of a phase III clinical trial showed that daridorexant significantly improved the total sleep time by comparison with placebo in the first and third months of treatment [87]. Daridorexant (7) received approval from the FDA on 7 January 2022 with the trade name Quviviq [88].

Gadopiclenol (Elucirem TM )
Gadopiclenol (8, Elucirem, Villepinte) is a paramagnetic, extracellular, nonspecific macrocyclic gadolinium-based contrast agent (GBCA) developed by Guerbet's Research and Development team. Gadopiclenol (8) is a large-membered cyclic compound, featuring a 3,6,9-triaza-1(2,6)-pyridinacyclodecaphane unit and glutaric moiety (Figure 2). Gadopiclenol develops a magnetic moment when placed in a magnetic field. The magnetic moment alters the relaxation rates of water protons in its vicinity in the body, leading to an increase in the signal intensity of tissues and enhancing the magnetic resonance imaging (MRI) quality for tissue differentiation in disease diagnosis. The FDA approved gadopiclenol (8) in September 2022 primarily based on data obtained from phase III studies showing that gadopiclenol could improve image quality in brain and body MRI at half the conventional gadolinium dose [90].
The precursor for the preparation of perfusion computerized tomography with acetazolamide challenge (PCTA) derivatives (including gadopiclenol) is the Gd complex of PCTA known as Gd(PCTA-tris-glutaric acid). Gadopiclenol (8) is obtained by amidation of the above compound with isoserinol [91,92]. Gd(PCTA-tris-qlutaric acid) has three stereocenters on the glutaric moieties, leading to eight possible stereoisomers. However, the chemical structure of gadopiclenol contains a total of six stereocenters, and the exact composition of the isomeric mixture obtained, isomer separation, and isomer characterization were not provided or disclosed.
The synthetic route for omidenepag isopropyl (9) is shown in Scheme 9 [109]. Compound 60 is reacted with 1-(4-(bromomethyl)phenyl)-1H-pyrazole in the presence of NaH in DMF under basic conditions, affording compound 61, which is then converted into omidenepag (58) via deprotection of the Boc and the t-Bu groups under acidic conditions. Further conversion of omidenepag (58) in the presence of hydrochloric acid gives the desired omidenepag isopropyl (9) as a white solid. sideration the above facts, SAR efforts were made by modifying the phenoxyacetic acid, pyridin-3-ylsulfonyl, and tert-butylphenyl moieties of compound 59. The results led to the development of omidenepag isopropyl (9), demonstrating potent and selective activity toward the human EP2 receptor (h-EP2) with an EC50 value of 1.1 nM. Omidenepag isopropyl (9) was approved by the FDA in September 2022 with the indication of reducing elevated intraocular pressure in patients with open-angle glaucoma, and it could thus be used as an ocular hypotensive agent for intraocular pressure (IOP). The synthetic route for omidenepag isopropyl (9) is shown in Scheme 9 [109]. Compound 60 is reacted with 1-(4-(bromomethyl)phenyl)-1H-pyrazole in the presence of NaH in DMF under basic conditions, affording compound 61, which is then converted into omidenepag (58) via deprotection of the Boc and the t-Bu groups under acidic conditions. Further conversion of omidenepag (58) in the presence of hydrochloric acid gives the desired omidenepag isopropyl (9) as a white solid.

Phenylbutyrate-Taurursodiol (Relyvrio TM )
Phenylbutyrate-taurursodiol (10, sodium phenylbutyrate/taurursodiol) is a fixeddose combination oral treatment developed by Amylyx Pharmaceuticals for slowing disease progression in amyotrophic lateral sclerosis (ALS) patients [110][111][112][113][114][115][116][117][118]. Taurursodiol (62), also known as tauroursodeoxycholic acid, is the bile acid taurine conjugate and a more hydrophilic form of ursodeoxycholic acid, produced naturally in the body ( Figure 6). Taurursodiol is responsible for improving mitochondrial energy production and anti-apoptotic effects [117,118]. Sodium phenylbutyrate is a salt of 4-phenylbutyric acid (4-PBA) [113] that is used to treat urea cycle disorders [114]; it acts as a chemical chaperone, preventing protein aggregation [115,116]. The combination of phenylbutyrate-taurursodiol was approved for medical use in Canada as Albrioza in June 2022 and in the USA as Relyvrio in September 2022 [119]. more hydrophilic form of ursodeoxycholic acid, produced naturally in the body ( Figure  6). Taurursodiol is responsible for improving mitochondrial energy production and antiapoptotic effects [117,118]. Sodium phenylbutyrate is a salt of 4-phenylbutyric acid (4-PBA) [113] that is used to treat urea cycle disorders [114]; it acts as a chemical chaperone, preventing protein aggregation [115,116]. The combination of phenylbutyrate-taurursodiol was approved for medical use in Canada as Albrioza in June 2022 and in the USA as Relyvrio in September 2022 [119].  Sodium phenylbutyrate is prepared by reacting phenylbutyric acid with a sodium base [120]. Tauroursodeoxycholic acid 62 is prepared by selective precipitation of the impurities present in the suspension obtained from the reaction of an aqueous solution of sodium taurinate with an acetonic solution of a mixed anhydride of ursodeoxycholic acid 63 with an alkyl chloroformate (Scheme 10) [121]. Sodium phenylbutyrate is prepared by reacting phenylbutyric acid with a sodium base [120]. Tauroursodeoxycholic acid 62 is prepared by selective precipitation of the impurities present in the suspension obtained from the reaction of an aqueous solution of sodium taurinate with an acetonic solution of a mixed anhydride of ursodeoxycholic acid 63 with an alkyl chloroformate (Scheme 10) [121].

Conclusions
From the standpoint of chemical structure, AAs represent an ideal platform for the rational design of modern pharmaceuticals. Thus, the presence of basic (amine) and acidic (carboxyl) functional groups, in combination with stereogenic carbon and practically unrestricted structural/functional space of the side chains, offers an extraordinary background for the design of a three-dimensional structural framework to achieve the desired biological functionality. Accordingly, one can expect that tailor-made AAs will continue to serve as indispensable building blocks in modern medicinal chemistry and drug design. As a result of the current and future importance of tailor-made AAs, there is clearly a fastgrowing need in the availability of various structural types of AAs. Thus, the interest in new approaches for the asymmetric synthesis of tailor-made AAs is currently at an alltime high [122,123]. Some breakthrough developments have been made in the area of dynamic kinetic resolution of unprotected AAs [124,125], which can be efficiently used for large-scale synthesis and can compete with biocatalytic approaches in terms of affordability and low-cost structure. Nevertheless, the application of AAs has some inherent problematic issues. Some of them are the racemization of the stereogenic carbon, proteolytic and microsomal metabolism, clearance rates, and membrane permeability of AA-derived drugs. Fortunately, these issues can be ameliorated by the rational substitution of fluorine for hydrogen and/or the incorporation of fluorine-containing groups. The steric, electronic, and physical properties of the fluorinated groups [126][127][128][129] can be rationally applied to enhance configurational stability, reduce proteolytic and microsomal degradation, slow down clearance rates, and enhance membrane permeability [130][131][132], allowing us to quite successfully address the intrinsic stumbling blocks associated with the application of AAs.

Conclusions
From the standpoint of chemical structure, AAs represent an ideal platform for the rational design of modern pharmaceuticals. Thus, the presence of basic (amine) and acidic (carboxyl) functional groups, in combination with stereogenic carbon and practically unrestricted structural/functional space of the side chains, offers an extraordinary background for the design of a three-dimensional structural framework to achieve the desired biological functionality. Accordingly, one can expect that tailor-made AAs will continue to serve as indispensable building blocks in modern medicinal chemistry and drug design. As a result of the current and future importance of tailor-made AAs, there is clearly a fast-growing need in the availability of various structural types of AAs. Thus, the interest in new approaches for the asymmetric synthesis of tailor-made AAs is currently at an all-time high [122,123]. Some breakthrough developments have been made in the area of dynamic kinetic resolution of unprotected AAs [124,125], which can be efficiently used for large-scale synthesis and can compete with biocatalytic approaches in terms of affordability and low-cost structure. Nevertheless, the application of AAs has some inherent problematic issues. Some of them are the racemization of the stereogenic carbon, proteolytic and microsomal metabolism, clearance rates, and membrane permeability of AA-derived drugs. Fortunately, these issues can be ameliorated by the rational substitution of fluorine for hydrogen and/or the incorporation of fluorine-containing groups. The steric, electronic, and physical properties of the fluorinated groups [126][127][128][129] can be rationally applied to enhance configurational stability, reduce proteolytic and microsomal degradation, slow down clearance rates, and enhance membrane permeability [130][131][132], allowing us to quite successfully address the intrinsic stumbling blocks associated with the application of AAs.