Synthesis and clinical application of new drugs approved by FDA in 2022

The pharmaceutical industry had a glorious year in 2022, with a total of 37 new drugs including 20 new chemical entities (NCEs) and 17 new biological entities (NBEs) approved by the Food and Drug Administration (FDA). These drugs are mainly concentrated in oncology, central nervous system, antiinfection, hematology, cardiomyopathy, dermatology, digestive system, ophthalmology, MRI enhancer and other therapeutic fields. Of the 37 drugs, 25 (68%) were approved through an expedited review pathway, and 19 (51%) were approved to treat rare diseases. These newly listed drugs have unique structures and new mechanisms of action, which can serve as lead compounds for designing new drugs with similar biological targets and enhancing therapeutic efficacy. This review aims to outline the clinical applications and synthetic methods of 19 NCEs newly approved by the FDA in 2022, but excludes contrast agent (Xenon Xe-129). We believe that an in-depth understanding of the synthetic methods of drug molecules will provide innovative and practical inspiration for the development of new, more effective, and practical synthetic techniques. According to the therapeutic areas of these 2022 FDA-approved drugs, we have classified these 19 NCEs into seven categories and will introduce them in the order of their approval for marketing. Supplementary Information The online version contains supplementary material available at 10.1186/s43556-023-00138-y.


Introduction
The pharmaceutical industry is constantly evolving, with new drugs being developed and approved by the FDA every year.These new drugs offer hope for patients suffering from various diseases and conditions, and they represent a significant advancement in medical science.In 2022, the FDA approved 37 new drugs that have the potential to revolutionize the treatment of various diseases.Of the 37 new drugs, 20 (54%) new drugs belong to new chemical entity (NCE), and 17 (46%) new drugs belong to new biological entity (NBE) [1].As shown in Table S1, we summarized the drug names, research & development companies, active ingredients, approval dates, indications, and other information of the 37 new drugs [2].By analyzing the approved drugs and their indications [3], it can be found that the main therapeutic field is still oncology, and 10 new oncologic drugs were approved (accounting for 27% of all approved drugs).Seven drugs were approved in the field of the central nervous system (accounting for 19% of the total), five drugs were approved in the field of dermatology (14%), four drugs were approved in the field of anti-infective (accounting for 11% of the total), and three drugs were approved in the fields of hematology (accounting for 8% of the total).Two drugs (5%) were approved in ophthalmology and metabolism respectively, and one drug (3% of the total) was approved in the digestive system and cardiomyopathy respectively.Of these 37 new drugs, up to 25 (68%), new drugs were reviewed and approved through the FDA Center for Drug Evaluation and Research (CDER) accelerated approval process.These accelerated approvals are divided into the following categories: fast track, accelerated approval, priority review, and breakthrough therapy.Among them, 18 new drugs received priority review, 9 new drugs obtained fast track, 4 new Drugs received accelerated approval and 13 new drugs obtained breakthrough therapy, including 6 NCEs and 7 NBEs.It is worth noting that 19 (51%) new drugs were approved to treat rare diseases: For example, Enjaymo is used for the treatment of cold agglutinin disease (CAD), a rare, chronic, serious, autoimmune hemolytic anemia disease [4,5]; Myelofibrosis (MF) is an uncommon condition characterized by abnormalities in the production of blood cells and the presence of fibrosis in the bone marrow [6], and Vonjo received approval to treat primary and secondary MF in adult patients who have experienced a substantial decrease in their platelet levels [7]; Amvuttra was approved by FDA to treat polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTR), a genetic condition resulting from mutations in the TTR gene [8,9].Compared with the 50 drugs approved by the FDA in 2021 (36 NCEs and 14 NBEs), although the number of drugs approved in 2022 is relatively small, there are still some remarkable achievements.For example, Tirzepatide is the first-in-class glucose-lowering drug approved in recent years with a new mechanism of action.In addition to type 2 diabetes, it has shown good potential for treating obesity.The HIV-1 capsid inhibitor lenacapavir can be taken once every six months.Deucravacitinib, a tyrosine kinase 2 inhibitor used to treat psoriasis, the dual-specificity antibody faricimab-svoa for the treatment of macular degeneration, and the antibody-drug conjugate mirvetuximab soravtansine-gynx targeting folate receptor alpha to treat platinum-resistant ovarian cancer have shown good market value.
As far as we know, the study of the synthetic methods of new chemical molecules and their mechanisms of action in clinical applications will greatly promote the development of new drugs, and the summary of newly introduced drugs will provide innovative and practical inspiration for new drug discovery [10][11][12][13][14][15][16][17][18][19][20].Therefore, the purpose of this review is to provide an overview of 19 NCEs approved by the FDA in 2022 (Fig. 1), with a focus on the synthesis of these drugs, their mechanism of action, and their potential benefits and risks.The logical sequence of this review will be to first provide an Fig. 1 Chemical structures of FDA-approved drugs in 2022 overview of the new drugs approved by the FDA in 2022 (Table S1), followed by a detailed analysis of the 19 NCEs.Finally, the review will conclude with a summary of the key findings and their implications for healthcare professionals.The review will be of great value to physicians, pharmacists, and other healthcare professionals who are involved in the treatment of patients with the diseases and conditions targeted by these drugs.

Oteseconazole (Vivjoa)
Oteseconazole, developed by Mycovia, was given priority review and approved by the FDA on April 26, 2022, which was sold under the brand name Vivjoa, to prevent recurrent vulvovaginal candidiasis (RVVC) in women with no reproductive potential [21,22].As an orally active anti-fungal agent, oteseconazole is a highly potent and selective inhibitor of Candida albicans CYP51 with a Ki value of below 39 nM, showing no significant effect on human CYP51 [23][24][25].Thanks to the tetrazole moiety, oteseconazole features high selectivity for fungal CYP51 over human P450s, effectively decreasing off-target interactions, which is obviously distinct from previously discovered azole antifungals [26].Compared with oteseconazole, triazole or imidazole-containing fluconazole or ketoconazole causes significant drug-drug interactions due to their effect on human CYPs [27][28][29].By targeting CYP5, oteseconazole blocks the transformation of lanosterol to ergosterol, a sterol necessary for the formation and maintenance of fungal cell membrane integrity, thus exerting antifungal activity toward RVVC-related microorganisms, including Candida dubliniensis, krusei, lusitaniae, albicans, tropicalis, glabrata and parapsilosis [30].Oteseconazole carries a risk of embryo-fetal toxicity and is therefore not permitted for use in women with reproductive potential [31,32].

Vonoprazan, amoxicillin, and clarithromycin (Voquezna)
Vonoprazan was first launched in Japan in February 2015 to treat acid-related diseases and as an adjunct to the eradication of Helicobacter pylori [34][35][36].As a potassium-competitive acid blocker (PCAB), vonoprazan blocks the secretion of gastric acid mediated by H + , K + -ATPase, which can be regarded as an alternative to proton-pump inhibitors to treat acid-associated disorders.CYP2C19 genetic polymorphisms show little effect on PCABs, which is obviously different from protonpump inhibitors [37].In addition, vonoprazan exhibits 350 times more active than lansoprazole, a proton pump inhibitor, which is attributed to its ability to accumulation in the gastric corpus mucosa, especially in parietal cells [38].In May 2022, Vonoprazan, in combination with clarithromycin and amoxicillin was approved to treat Helicobacter pylori infection [39].These approvals are based on the safety and effectiveness data of phalcon-hp phase 3 trial, which is the largest registered trial ever conducted in the United States in Helicobacter pylori, and 1046 patients were randomly assigned [40].In the improved intention to treat population, the two vonoprazan treatment regimens showed no worse than lansoprazole triple therapy in patients without clarithromycin or amoxicillin resistant Helicobacter pylori strains at baseline [41].The combination of amoxicillin, vonoprazan and clarithromycin has been reported to result in an eradication rate of Helicobacter pylori of about 90% [42,43].

Lenacapavir (Sunlenca)
Lenacapavir, a first-in-class picomolar inhibitor of HIV-1 capsid protein, is used as a monotherapy, featuring little cross-resistance with clinically used antiretroviral agents and extended pharmacokinetics [48,49].The European Commission granted the first worldwide approval of Lenacapavir to treat adults with multidrugresistant HIV infection on 22 August 2022.On December 22, 2022, it also received FDA approval to treat HIV patients [50,51].Lenacapavir exhibits its anti-HIV-1 activity through blocking the viral replication of HIV-1 virus, which is closely related to many processes of viral lifecycle: uptake, assembly, and release [52].The lenacapavir's difluorobenzyl ring and CPSF6/Nup153 share the same binding pocket, with the benzyl groups of F1417 and F321 overlapping [53].The crystal structure reveals that six lenacapavir molecules establishes a wide range of interactions with the protein, including cation-π interactions, hydrophobic interactions, and hydrogen bonds, thereby interrupting capsid interactions with CPSF6 and Nup153.In multiple cell lines, in vitro HIV-1 replication inhibition assays show EC 50 values of ~ 12-314 pM.Lenacapavir exhibits different inhibitory effect at low and high concentrations: it blocks viral nuclear entry at 0.5 nM, while inhibits the reverse transcription and DNA synthesis at 5-50 nM [54].

Daridorexant (Quviviq)
Daridorexant, the second orexin receptor antagonist after suvorexant, was approved by the FDA on January 10, 2022, for clinical use to treat adult insomnia patients with difficulties of sleep maintenance and/or sleep onset [56,57].It was then approved by the European Commission on 3 May 2022, making it the first dual orexin receptor antagonist to be approved for marketing [58].Daridorexant potently inhibits orexins by working on OX1R and OX2R (Ki = 0.47 and 0.93 nM, respectively), which are wake-promoting endogenous ligands and neuropeptides [59].Daridorexant is found to decrease overactive wakefulness.Daridorexant has been reported to improve daytime functioning and sleep in insomnia patients [60].Before the approval of daridorexant, two orexin receptor antagonists have been marketed, including Mercer's suvorexant (approved in 2014) and Eisai's lemborexant (approved in 2019) [61].But neither has fared well in the market so far.
The synthesis of daridorexant is outlined in Fig.

Ganaxolone (Ztalmy)
Developed by Marinus, Ganaxolone was granted FDA approval as the inaugural treatment specifically indicated for seizures in cyclin-dependent kinase-like 5 deficiency disorder (CDD) [63,64].Ganaxolone is one of the metabolites of progesterone from 3β-methylation of allopregnanolone [63].Ganaxolone, a new class of neuroactive steroids, is effective positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors [65], which has specific and potent efficacy, like its endogenous counterparts [66].Ganaxolone exerts its effect by binding to one specific allosteric binding site of GABAA, which is different from that of benzodiazepine [67].It is characterized by analgesic, sedative, anxiolytic, hypnotic, anticonvulsant, and anesthetic properties [68].It is important to note that antiepileptic medications may increase the risk of suicidal ideation and suicidal behavior, and caution should be taken when considering treatment with ganaxolone [69][70][71].

Sodium phenylbutyrate/taurursodiol (Relyvrio)
Phenylbutyric acid, a fatty acid derivative of butyric acid produced by natural fermentation of colon bacteria, has many cellular and biological effects, such as easing inflammation, which is used to treat neurological or urea cycle disorders and inherited metabolic syndrome [75].Sodium phenylbutyrate is a prodrug of phenylacetic acid that quickly metabolizes to its original style [76].Then, phenylacetate binds to phenylacetyl-CoA, which is subjected to acetylation to give phenylacetylglutamine, which is ultimately excreted by the kidneys [77].In Europe, taurursodiol, a taurine conjugate of ursodeoxycholic acid, is utilized for the prevention and treatment of gallstones due to its antiapoptotic and inhibitory effects on ER stress response [78].Furthermore, taurursodiol has been also investigated in neurodegenerative and inflammatory metabolic diseases due to its array of molecular properties, such as anti-apoptotic effects [79,80].Taurursodiol effectively decreases the body cholesterol content and intake of dietary cholesterol by reducing intestinal absorption of cholesterol [81].Relyvrio, an FDA-approved treatment for amyotrophic lateral sclerosis (ALS), is a blend of sodium phenylbutyrate and taurursodiol [82,83].ALS is so deadly that most patients have a life expectancy of only 3 to 5 years after onset of symptoms, and they typically die from respiratory failure, a progressive atrophy of the muscles used for respiration [84][85][86][87].Relyvrio received early FDA approval due to the highly progressive nature and serious threat of ALS.However, Relyvrio prolong patients' survival by slowing progression but not cure disease [88,89].

Abrocitinib (Cibinqo)
On December 10, 2021, abrocitinib was initially approved by the European Commission to treat adult patients with atopic dermatitis (AD) [91,92].On January 14, 2022, abrocitinib received the FDA approval to treat patients with refractory moderate-to-severe AD who have limited or little response to other systemic drugs [93].Abrocitinib potently and selectively inhibits JAK1 with an IC 50 value of 29 nM, which is better than that of JAK2 (IC 50 = 803 nM).Abrocitinib exerts antiinflammatory effects by blocking pro-inflammatory cytokine signaling associated with atopic dermatitis [94].It effectively decreases serum markers of atopic dermatitis inflammation in a dose-dependent manner, including interleukin-31 (IL-31), thymus and activation-regulated chemokine (TARC), and high-sensitivity C-reactive protein (hsCRP) [95].Mean absolute lymphocyte counts increased during two weeks of treatment and returned to baseline after 9 months of treatment [93,96,97].According to the Phase 3 results, the experimental group showed significant improvement in disease extent, severity, and skin clarity compared to the placebo group, and patients were able to rapidly relieve itching symptoms after two weeks treatment [94].It is one of the first oral JAK inhibitors for AD in the United States, and previously received FDA breakthrough treatment and priority review qualifications [98].
The total synthesis of tapinarof is depicted in Fig. 4 [112].Methylation of commercially available dimethyl sulfate with 3,5-dihydroxybenzoic acid (TAPI-001), followed by reaction with isopropyl alcohol in the presence of 60% ~ 80% concentrated sulfuric acid, giving TAPI-003.Subsequently reduction of carboxyl forms alcohol TAPI-004.Next, chlorination of TAPI-004 with hydrochloric acid provides TAPI-005, which then undergoes Wittig-Horner condensation to generate compound TAPI-006.TAPI-006 reacts with benzaldehyde in the presence of NaH and THF under nitrogen atmosphere, affording TAPI-007, which is subjected to demethylation catalyzed by pyridine hydrochloride to afford the target compound tapinarof.

Deucravacitinib (Sotyktu)
On September 9, 2022, Deucravacitinib was approved by the FDA to treat moderate-to-severe plaque psoriasis [113].Deucravacitinib, a member of the Janus kinase (JAK) family, is a highly potent allosteric inhibitor of tyrosine kinase 2 (TYK2) with an IC 50 value of 1.0 nM [114].It stabilizes an inhibitory interaction between catalytic and regulatory domains of the enzyme, which blocks the activation of Signal Transducers and Activators of Transcription (STATs) and TYK2in cell-based assays [115][116][117].The precise mechanism by which inhibiting the TYK2 enzyme leads to effective treatment in patients with moderate-to-severe plaque psoriasis is still not fully understood.However, its mechanism is different from other Janus kinase inhibitors targeting the conserved active domain, thereby exerting its high selectivity toward TYK2 [118], which is expected to avoid various adverse effects caused by non-selective JAK inhibitors, such as kidney and liver dysfunction, and altered triglyceride and cholesterol level.

Mitapivat (Pyrukynd)
Mitapivat is the first orally active pyruvate kinase allosteric activator, which was approved by FDA on February 17, 2022, to manage hemolytic anemia in individuals with pyruvate kinase (PK) deficiency [120][121][122].Mitapivat activates PK through allosteric regulation, binding to a distinct allosteric site on the PKR tetramer separate from fructose bisphosphate FBP [123].The red blood cell (RBC) form of PK is mutated in PK deficiency, resulting in shortened RBC lifespan, reduced adenosine triphosphate (ATP), and chronic hemolysis [124].Mitapivat increases its affinity for its substrate and stabilizes phosphoenolpyruvate by binding to pyruvate kinase [120].Mitapivat increases ATP production and erythrocyte pyruvate kinase activity (wild-type and mutant forms) but reduces levels of 2,3-DPG [123].Mitapivat has also been investigated in other genetic disorders affecting red blood cells and causing hemolytic anemia, such as α-/βthalassemia and sickle cell disease [123].
Pacritinib demonstrates a dose-dependent suppression of signal transducer and activator of transcription 5 (STAT5) phosphorylation in expanded erythroid progenitor cells obtained from healthy individuals [131].A single 400 mg dose of pacritinib moderately inhibits STAT3 phosphorylation induced by interleukin 6 in the whole blood of healthy subjects [132,133].Pacritinib is administered orally twice daily and is contraindicated in patients with renal insufficiency and hepatic insufficiency.It offers an alternative for MF patients with severe thrombocytopenia, commonly carrying a pretty poor prognosis [134].

Lutetium ( 177 Lu) vipivotide tetraxetan (Pluvicto)
As a radioligand therapeutic agent, lutetium ( 177 Lu) vipivotide tetraxetan consists of a radionuclide, lutetium Lu-177, conjugated to a prostate-specific membrane antigen (PSMA)-binding moiety, exercising cytotoxic effect on cancer cells [138,139].The β-negative emission of lutetium Lu-177 irradiates PSMA-expressing cells and surrounding cells, thereby inducing DNA damage and cell death.In a clinical trial, it was discovered that Lutetium ( 177 Lu) vipivotide tetraxetan exhibited a significant correlation with an 80.4% decrease in serum PSA levels.Additionally, the median progression-free survival for these patients was determined to be 13.7 months [140].Following other therapies, it was granted FDA approval on March 23, 2022, to treat metastatic castration-resistant prostate Fig. 5 Synthesis of mitapivat and pacritinib cancer with prostate-specific membrane antigen positivity [141].This approval is based on the positive results of phase 3 clinical trial, which showed that the addition of Pluvicto reduced the risk of patient death by 38% compared to standard therapy and that Pluvicto also significantly reduced the risk of patients developing radiographic disease progression or death [142].Furthermore, in patients with evaluable disease at baseline, the overall remission rate was 30% in the Pluvicto group, compared to 2% in the standard treatment control group [143].In October 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a recommendation for the authorization of marketing for a therapeutic intervention targeting prostate cancer [144].

Futibatinib (Lytgobi)
On September 30, 2022, the FDA granted approval to Futibatinib, a permanent inhibitor of Fibroblast Growth Factor receptor (FGFR), for the treatment of intrahepatic cholangiocarcinoma that contains FGFR2 gene fusions or other genetic rearrangements [147].Futibatinib effectively inhibits FGFR 1-4 (IC 50 = 3.9, 1.3, 1.6, and 8.3 nM), respectively, by forming a covalent bond with cysteine in the ATP-binding pocket of FGFR kinase domain [148][149][150].In addition, Futibatinib exhibits similar inhibitory potency toward wild-type (WT) and mutant FGFR2 with IC 50 values of 0.9 nM, 1-3 nM, 3.6 nM, and 2.4 nM against WT FGFR2, V5651, N550H, and E566G, respectively [148][149][150].FGFR plays a crucial role in cell differentiation, survival, proliferation, and migration, and aberrant signaling pathways and genomic aberrations commonly occur in a variety of cancers since the survival and proliferation of malignant cells can be supported by FGFR signaling [148,151].Futibatinib efficiently inhibits the phosphorylation of FGFR and subsequent signaling pathways.This inhibition leads to a decrease in the survival of cancer cells harboring FGFR rearrangements, fusions, mutations, and amplifications in xenograft models derived from mice and rats [152].In the end, futibatinib effectively decreases the survival of cancer cells with FGFR alterations, such as FGFR fusions or rearrangements, amplifications, and mutations [153].

Olutasidenib (Rezlidhia)
On December 1, 2022, the FDA granted approval to olutasidenib, a highly effective inhibitor of isocitrate dehydrogenase-1 (IDH1), to treat relapsed or refractory acute myeloid leukemia (AML) in adults who possess a susceptible IDH1 mutation [155,156].Normally, IDH1 catalyzes mediated the conversion of isocitrate to α-ketoglutarate (α-KG) through oxidative decarboxylation reaction [157].However, IDH1 mutations are commonly observed in the catalytic sites of arginine in various cancers, such as AML, and stimulate the transfer of α-KG to 2-hydroxyglutarate (2-HG) [158].This leads to 2-HG increase, which is closely related to the inhibition of α-KG-dependent mechanisms, such as collagen synthesis, epigenetic regulation, and cell signaling.Olutasidenib effectively decreases 2-HG levels by selectively targeting mutant IDH1, leading to the restoration of normal cell differentiation and offering therapeutic advantages in IDH1 mutant strains.Additionally, olutasidenib is currently investigated to treat myelodysplastic syndromes (MDS), as well as solid tumors and gliomas (NCT03684811) [159][160][161].

Adagrasib (Krazati)
Adagrasib, an orally bioavailable inhibitor of KRAS, was developed by Mirati.On December 12, 2022, Therapeutics obtained accelerated FDA approval to treat KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer in adults who have undergone at least one prior systemic therapy [163][164][165].Normally, activation of KRAS through binding to guanosine triphosphate (GTP) stimulates the activation of intracellular signal transduction and MAP kinase pathway.Hydrolyzation of GTP gives guanosine diphosphate (GDP) and KRAS restores the inactive state [166].Cysteine substitution of Gly12 in KRAS (KRASG12C) damages GTP hydrolysis and keeps KRAS in active form, which results in uncontrolled cell growth and proliferation as well as malignant transformation [167].Adagrasib covalently and selectively binds to KRASG12C and locks it in the inactive state, thus exerting anti-tumor activity by inhibiting tumor cell viability and growth [168].

Mavacamten (Camzyos)
Mavacamten was approved by US FDA in 2022, which is used to treat adult patients with obstructive hypertrophic cardiomyopathy (oHCM) who are experiencing symptoms and fall into New York Heart Association (NYHA) class II-III [171,172].Mavacamten is a medication that can be taken by mouth.It acts as an inhibitor of cardiac myosin, which is a protein involved in muscle contraction in the heart.This medication works by regulating the number of myosin heads that can enter the "on actin" states, effectively reducing the likelihood of generating force during systole (contraction) and residual force during diastole (relaxation) across the bridge.Additionally, its inhibitory effects are reversible, meaning that its action can be reversed if necessary [173].HCM is characterized by the presence of excessive formation of myosin actin bridges and dysregulation of the hyperrelaxation state [174].Mavacamten transforms the total amount of myosin into an energy-saving, absorbable, ultra-relaxed state [175].Inhibition of myosin with Mavacamten reduced dynamic left vein obstruction and improved cardiac filling pressure in patients with HCM.It has been reported that the IC 50 values of Mavacamten in the bovine, human, and rabbit system are 490 nM, 711 nM, and 2140 nM, respectively, indicating a 4-fold selectivity for myocardial myosin [176][177][178].Mavakamten is found to reduce contractility through decreasing the activity of adenosine triphosphatase in the heavy chain of myocardial myosin [179].Long-term administration results in the inhibition of the development of myocardial cell disorders, myocardial hypertrophy, and myocardial fibrosis, and attenuates the gene expression of profibrotic and hypertrophic in mice featuring heterozygous human mutations in the chain of myosin heavy [176].

Terlipressin (Terlivaz)
Terlipressin, a medication aimed at enhancing kidney function in adult patients with hepatorenal syndrome experiencing a rapid decline in kidney function, obtained FDA approval on September 14, 2022 [181,182].
Terlipressin, an analog of vasopressin, is an endogenous neurohormone that acts as a vasoconstrictor [183][184][185][186][187][188].As a prodrug of lysine-vasopressin, terlipressin itself is pharmacologically active, characterized by a longer halflife and higher selectivity for V1 receptor than vasopressin, which controls acute variceal bleeding, and reduces the splanchnic blood flow and portal pressure [189].These favorable pharmacokinetic and molecular properties of terlipressin confer several advantages, such as convenience in patients with limited intravenous access and prevention of rebound hypotension upon discontinuation [188,190].

Gadopiclenol (Elucirem)
Gadopiclenol, a gadolinium-based contrast agent (GBCA), was developed by Guerbet.On September 21, 2022, after undergoing a priority review, the FDA granted its approval to the product.Its primary objective is to identify and display abnormal vascularity lesions in the body and the central nervous system, in combination with magnetic resonance imaging (MRI).In 2006, linear GBCA use was linked to nephrogenic systemic fibrosis (NSF) [192][193][194], a rare disease characterized by hardening and thickening of the subcutaneous and skin tissue, which has not been detected in macrocyclic GBCAs, such as gadopiclenol [195].It should be noted that in NSF patients with impaired drug clearance, a black box warning was given to gadopiclenol to remind an increased risk.Gadopiclenol carries two water molecule exchange sites for increased relaxation and contrast [195].Compared with other non-specific GBCAs, gadopiclenol dose is only half of the conventional gadolinium dose, alleviating practitioners' concerns about radiation exposure [196].Variations in radiofrequency signal strength allow visualization of normal and pathological tissue during MRI, which is characterized by the differences in longitudinal relaxation times (T1) or spin-lattice, proton density, or in transverse relaxation times or spin-spin (T2).The T1 and T2 relaxation times can be shortened by Gadopiclenol, resulting in the visualization of target tissues during MRI [197].The extent of a contrast agent affecting the tissue water relaxation rate (1/T1 or 1/T2) is expressed in terms of the relaxation rate (r1 or r2).The high r1 relaxation rate and kinetic stability of gadopiclenol allow it to be used at lower doses than traditional extracellular GBCAs.What deserves special vigilance is that acute kidney injury and hypersensitivity reactions may also occur with gadopiclenol [198].

Omidenepag isopropyl (Omlonti)
Omidenepag isopropyl, approved in Japan in 2018 as a potent agonist of EP2 receptor to treat ocular hypertension and glaucoma [200], was then approved by FDA on September 22, 2022, to lower high intraocular pressure in individuals diagnosed with ocular hypertension or open-angle glaucoma.Omidenepag isopropyl is rapidly metabolized to its active metabolite omidenepag, which binds strongly to prostaglandin E2 (EP2) receptor (Ki = 3.6 nM) [201].Furthermore, Omidenepag is highly agonistic at the EP2 receptor (EC 50 = 8.3 nM) but has little effect on other receptors such as prostaglandin E1 (EP1) or F receptors (FP) [200,202,203].Unlike omidenepag, omidenepag isopropyl has little or no affinity for prostaglandin receptors [200,203].EP2 receptor exists in different kinds of ocular tissues related to aqueous humor dynamics, such as ciliary muscle (CM) and trabecular meshwork (TM) [204].Stimulation of EP2 receptors may result in increased intracellular cyclic adenosine monophosphate (cAMP), leading to relaxation of CM and TM tissues [205].Omidenepag has shown comparable efficacy in lowering IOP to latanoprost, a prostaglandin FP receptor agonist, which is a first-line treatment for primary ocular hypertension and open-angle glaucoma [206].

Conclusion and prospect
In conclusion, in 2022, FDA approved 37 new drugs, including 20 NCEs, 7 monoclonal antibodies (mAbs), 3 bispecific antibodies (BsAbs), 2 enzymes, 1 fusion protein, 1 synthetic polypeptide, 1 small interfering RNA (siRNA), 1 toxin, 1contrast agent and a colony stimulating factor (CSF).In the context of the COVID-19 pandemic, FDA is still committed to supporting the development of rare disease drugs.The field of antitumor is still a hot area for innovative drug development.These approved new drugs will benefit patients suffering from orphans, cancer, nervous system diseases, infectious diseases, and many other diseases.
In this review, we summarized the clinic application and synthetic routes of the 19 NCEs of new drugs approved by the FDA.The pharmacophore library will be enriched and new drug discovery will be benefited by the presence of privileged scaffolds in these drug molecules.For example, me-better drug omidenepag isopropyl is developed based on the molecular structure of CP-533,536, which was reported by previous researchers and optimized through the structural modification of PGE2 [202].The AIDS prevention drug lenacapavir is developed based on the structure of PF-3450074.In order to block the unstable metabolic site, researchers focused on introducing electron-withdrawing groups (halogens and sulfonyl groups) and metabolically stable rigid ring systems (cyclopropane and pyrazole) through optimization [207].Both deucravacitinib and olutasidenib were first screened through high-throughput screening to obtain lead compounds, and their solubility was improved through SBDD.Adagrasib has increased its in vitro stability in whole blood (WB) by introducing a fluorine atom at the 2-position of acrylamide [208].
In addition, we discovered that metal-catalyzed coupling reactions were utilized in the synthesis of pharmaceuticals (such as omidenepag, futibatinib, oteseconazole, etc.).Chiral resolution and asymmetric synthesis were employed for obtaining the single enantiomer of the chiral drugs (such as taurursodiol, ganaxolone, and oteseconazole, etc.).Other traditional organic synthetic strategies, such as substitution reaction, hydrolysis reaction, Curtius rearrangement, and addition reaction were still used for the synthesis of these new drug molecules approved by the FDA.The special skeletons in the drug molecules enrich the effective pharmacophores, which will help to design new drugs.