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. 2023 Nov 7;15(21):2011–2023. doi: 10.4155/fmc-2023-0207

Pyrazole: an emerging privileged scaffold in drug discovery

Mohammad Abrar Alam 1,*
PMCID: PMC10652296  PMID: 37933613

Abstract

Pyrazole or 1H-pyrazole, a five-membered 1,2-diazole, is found in several approved drugs and some bioactive natural products. A myriad number of derivatives of this small molecule have been reported in clinical and preclinical studies for the potential treatment of several diseases. The number of drugs containing a pyrazole nucleus has increased significantly in the last 10 years. Some of the best-selling drugs in this class are ibrutinib, ruxolitinib, axitinib, niraparib and baricitinib, and are used to treat different types of cancers; lenacapavir to treat HIV; riociguat to treat pulmonary hypertension; and sildenafil to treat erectile dysfunction. Several aniline-derived pyrazole compounds have been reported as potent antibacterial agents with selective activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Here, we discuss the pyrazole-derived drugs reported up to September 2023.

Keywords: antibacterial, anticancer, indazole, kinase inhibitor, lenacapavir, MRSA, pyrazole, sildenafil, zavegepant

Graphical abstract

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Pyrazole or 1H-pyrazole (1) is a five-membered 1,2-diazole (Figure 1). Substituted pyrazole and its derivatives are known for a wide spectrum of biological and therapeutic activities. Mono-, di- and tri-substituted pyrazole derivatives as well as their quaternary salts are integral parts of several drugs [1,2]. Pyrazole nucleus fused with a benzene ring such as 1H-indazole (indazole or 1,2-benzopyrazole, 2) is found in some natural products, several drugs and a large number of bioactive derivatives [3–5]. Similarly, 2H-indazole (3) and pyrazolo[1,5-a]pyridine (4) are an integral part of several drugs and numerous bioactive compounds such as antimalarials [6], antineoplastic [7], antibacterials [8] and so on [9–13].

Figure 1. . Structure of pyrazole (1) and its fused variants: 1H-indazole (2), 2H-indazole (3) and pyrazolo[1,5-a]pyridine (4).

Figure 1. 

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Several pyrazole-derived drugs have been reported in recent decades. Surprisingly, most pyrazole-containing drugs have been reported after 2016, as can be seen in the timeline (Figure 2). Here we will discuss the pyrazole-derived drugs reported up to September 2023.

Figure 2. . Timeline of approval of pyrazole containing in the USA.

Figure 2. 

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Pirtobrutinib (5) or Jaypirca® is one of the most recently approved drugs that received accelerated approval in January 2023. This tetra-substituted pyrazole derivative is a Bruton's tyrosine kinase inhibitor (TKI) approved to treat ibrutinib-resistant mantle cell lymphoma [14,15]. Zavegepant (6, Zavzpret™) is an indazole-substituted drug approved in 2023 to treat migraine. It is an antagonist of calcitonin gene-related peptide receptor (Figure 3) and used as a nasal spray [16]. This indazole derivative is the first intranasal third-generation gepant [17]. Lenacapavir (7, Sunlenca®) is a fused pyrazole-containing antiretroviral drug approved in 2022 to treat HIV/AIDS. It is the first capsid inhibitor – blocking the HIV-1 protein shell – that is approved to treat any disease to date. Lenacapavir (7) is being used to treat multidrug-resistant HIV-1 infection [18,19]. One of the unique properties of this polyfluorinated pyrazole-containing drug is its extra-long half-life, which needs a dosing interval of every 6 months [20]. Futibatinib (8, Lytgobi®), a kinase inhibitor, was approved in late 2022 to treat locally advanced and metastatic bile duct cancer (cholangiocarcinoma). This pyrimidine-fused pyrazole derivative (8) is being used to handle previously treated cholangiocarcinoma harboring FGF receptor 2-mutated or -rearranged genes [21,22]. Omidenepag isopropyl (9, Eybelis® and Omlonti®) has been approved to treat glaucoma and ocular hypertension. This drug was approved in Japan followed by the USA in 2018 and 2022, respectively. Omidenepag isopropyl (9) is a prodrug that is hydrolyzed to its active form, omidenepag.

Figure 3. . Pyrazole-derived drugs approved in recent years.

Figure 3. 

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Chronic myelogenous leukemia arises from the fusion of BCR and ABL1 genes on the Philadelphia chromosome from a reciprocal translocation between chromosomes 9 and 12. Some adult acute lymphatic leukemia cases arise from the same mechanism. Asciminib (10) has been discovered as the first allosteric BCR-ABL1 inhibitor to reach the clinic and has been approved to treat Philadelphia-positive chronic myelogenous leukemia (Figure 3). This pyrazole-substituted pyridine derivative (10) is a kinase inhibitor [23,24]. Vericiguat (11, Verquvo®) is a fused pyrazole-derived drug used to treat patients with heart failure. This small-molecule drug is a soluble guanylate cyclase stimulator that was approved in 2021 by the US FDA [25]. Belumosudil (12, Rezurock®) is a 1,2-benzopyrazole (indazole) drug that has been approved to treat chronic graft-versus-host disease caused by the complications of allogeneic hematopoietic cell transplantation. This pyrazole indazole-pyrimidine hybrid drug (12) has a dual and unique mechanism of action: it targets ROCK2 in T helper follicular cells and inhibits tissue fibrosis by inhibiting the Rho-ROCK-MRTF pathway [26].

Umbralisib (13, Ukoniq®, TG Therapeutics, NC, USA) is pyrazole-fused pyrimidine derivative that was approved on 5 February 2020 to treat refractory or relapsed marginal zone lymphoma and follicular lymphoma. It inhibits several kinases including casein kinase CK1-ε and PI3K-δ [27,28]. Berotralstat (14, Orladeyo®) was approved in 2020 to treat hereditary angioedema. This trifluoromethyl-attached trisubstituted pyrazole derivative (14) is a potent plasma kallikrein inhibitor and highly selective over related serine proteases [29,30]. Pralsetinib (15, Gavreto®) is a potent and selective inhibitor of RET receptor tyrosine kinase, which has been approved to treat non-small cell lung carcinoma (NSCLC) and thyroid cancer [31–33]. This small molecule drug contains two pyrazole units with fluorine and methyl substitutions. Selpercatinib (16, Retevmo®) has been approved by the FDA in 2020 to treat three types of cancer: NSCLC, medullary thyroid cancer and other thyroid cancers with RET gene altercations. This pyrazolo–pyridine hybrid is the first drug approved to treat cancer with a RET gene mutation or fusion, which accounts for approximately 2% of all human cancers [34]. These two pyrazole-based RET inhibitors, pralsetinib (15) and selpercatinib (16), have opened up a new paradigm of RET precision oncology [34]. Avapritinib (17, Ayvakit™) is an N-methyl pyrazole-substituted drug used to treat advanced systemic mastocytosis including aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm and mast cell leukemia (MCL). This drug is an orally available, potent and selective inhibitor of KIT (a receptor tyrosine kinase proto-oncogene) and PDGF receptor-α [35,36]. Voxelotor (18, Oxbryta) is an N-isopropyl substituted pyrazole-containing small-molecule drug approved to treat sickle cell disease. It inhibits the polymerization of deoxygenated sickle hemoglobin, polymerization of sickle hemoglobin drives sickle cell disease [37,38]. Voxelotor (18) is one of the rare drugs with an aldehyde functional group. Zanubrutinib (19, Brukinsa®) is an anticancer drug built on the core structure of the pyrazole nucleus. It is an irreversible, potent and highly selective covalent inhibitor of Bruton's tyrosine kinase [39]. This orally available small molecule has been approved to treat different types of B-cell malignancies [40]. Zanubrutinib (19) is a pyrazole–pyrimidine hybrid molecule containing a N-acryl warhead for covalent binding. Elexacaftor (20) is a cystic fibrosis transmembrane conductance regulator modulator dipyrazole-containing drug approved to treat cystic fibrosis. It is used along with ivacaftor and tezacaftor as a combination therapy (Trikafta®) [41]. Enterectinib (21, Rozlytrek®) is an indazole-containing drug used to treat several types of cancer. It is an ATP-competitive TKI with activity against ALK, ROS1, TRKA, TRKB and TRKC [42].

Darolutamide (22, Nubeqa™) is a small-molecule anticancer drug containing two pyrazole units (Figure 4). This dipyrazole-containing drug is used to treat castration-resistant prostate cancer. It is a structurally unique nonsteroidal androgen receptor antagonist [43]. Erdafitinib (23, Balversa™) is a TKI specifically targeting FGF receptor to treat different types of cancers. This small molecule has been approved to treat metastatic urothelial (bladder) cancer [44] and it (23) contains an N-methyl pyrazole moiety. Baricitinib (24, Olumiant™) is a disubstituted pyrazole derivative that has been approved to treat several diseases such as alopecia, COVID-19 and rheumatoid arthritis and is an inhibitor of several subtypes of Janus kinases. This molecule is also effective against adult-onset Still's disease, an idiopathic systemic inflammatory disease of unknown etiology [45–47]. Encorafenib (25, Braftovi®) is a trisubstituted pyrazole derivative that acts as a BRAF inhibitor to target MAP signaling pathways. This small-molecule pyrazole derivative (25) was approved in 2018 to treat BRAF V600E- or V600K-mutated melanoma [48]. Larotrectinib (26, Vitrakvi®) is a fused pyrimidine-pyrazole derivative approved in 2016 to treat metastatic solid tumors and is an inhibitor of tropomyosin kinase receptors (Trk A, B and C) [49]. This is the first drug specifically approved for tumors based on their specific mutation rather than their origin [50]. Lorlatinib (27, Lorbrena®) is a pyrazole-substituted macrolactam derivative that is an orally available ALK and ROS1 inhibitor used to treat ALK-positive metastatic NSCLC [51]. Edaravone (28, Radicava®) is a pyrazolone derivative approved to treat stroke and amyotrophic lateral sclerosis that was approved in 2016. Interestingly, this small molecule has been used as a biochemical reagent for a long time to analyze monosaccharides in carbohydrate complex media [52]. Niraparib (29, Zejula®) is a 2H-indazole derivative showing potent inhibition of PARP inhibitors with selective activity against PARP1 and PARP2. The FDA approved this drug in 2017 to treat recurrent epithelial ovarian and fallopian tube cancer [53,54]. Telotristat ethyl (30, Xermelo®) is an ester prodrug approved to treat diarrhea caused by carcinoid syndrome (Figure 4); this disubstituted pyrazole derivative (30) is a tryptophan hydroxylase inhibitor [55,56].

Figure 4. . Recently approved pyrazole-based drugs.

Figure 4. 

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Two pyrazolium-containing antibiotics, cefoselis (31) and ceftolozane (32), have been approved to treat bacterial infections (Figure 5). The zwitterion ion structure of these antibiotics helps to traverse the outer membrane of Gram-negative bacteria. Cefoselis (31) is a fourth-generation cephalosporin antibiotic used to treat respiratory and urinary tract infections [57]. Ceftolozane (32), a fifth-generation cephalosporin antibiotic containing a tetra-substituted pyrozolium moiety, is one of the most widely used antibacterial agents to treat drug-resistant bacterial infections including methicillin-resistant Staphylococcus aureus (MRSA), enterobacterales and Pseudomonas aeruginosa [58]. Ceftolozane (32), in combination with a bacterial β-lactamase inhibitor (tazobactam), is used to treat urinary tract infection, bacterial pneumonia and intra-abdominal infection. The pyrazolium nucleus is the key component of these antibiotics to prevent hydrolysis of the lactam moiety by AmpC β-lactamase [59]. Ibrutinib (33, Imbruvica®) is an irreversible inhibitor of BRTK approved in 2013 to treat mantle cell lymphoma. This pyrazole–pyrimidine hybrid molecule has been approved to treat mantle cell lymphoma, chronic lymphocytic leukemia and Waldenström's macroglobulinemia as a first-generation BRTK inhibitor [60]. Apixaban (34, Eliquis) is a fused pyrazole compound approved in 2012 in the USA as an anticoagulant medication to prevent blood clots; it is an inhibitor of factor Xa and an alternative to warfarin. This orally available drug was the 48th most prescribed medicine in the USA in 2020 [61,62]. Crizotinib (35, Xalkori®) is a disubstituted pyrazole derivative that was approved in 2011 to treat NSCLC and its mode of action is similar to that of lorlatinib (27) [63,64]. Ruxolotinib (36, Jakafi®) is a disubstituted pyrazole-derived drug approved in 2011 to treat myelofibrosis. This Janus kinase inhibitor has also been approved to treat other diseases such as intolerance of hydroxy urea and steroid-refractory acute graft-versus-host disease [65,66]. Ruxolitinib (36) is the first drug approved to treat alopecia and repigmentation of vitiligo [67].

Figure 5. . Pyrazole-derived compounds approved as drugs prior to 2017.

Figure 5. 

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Eltrombopag (37, Promacta®) is a pyrazolone-derived hydrazone derivative used to treat thrombocytopenia. This unique thrombopoietin receptor agonist was approved in the USA in 2008 [68,69]. Celecoxib (38, Celebrex®) was approved in 1999 as a COX-2 inhibitor to treat several inflammatory diseases. This trisubstituted pyrazole derivative is one of the top 100 bestselling drugs in the USA [70,71]. Sildenafil (39, Viagra®) is a pyrimidine-fused pyrazole derivative used to treat erectile dysfunction and pulmonary heart disease. This blockbuster drug is a phosphodiesterase-5 blocker used to regulate blood in the penis. This orally available, serendipitously discovered drug was approved in 1998 [72]. Granisetron (40, Kytril® or Sancuso®) is a selective 5-HT3R antagonist and a longer acting drug used to treat chemotherapy-induced nausea and vomiting. This indazole drug (40) was approved in the 1990s and can be administered by mouth, intravenously or transdermally [73,74]. Benzydamine (41) is a selective prostaglandin synthetase inhibitor that was approved in the 1990s for prophylactic treatment of oral mucositis caused by radiation therapy for head and neck cancer [75]. This indazole drug also works as a central nervous system stimulant and is often used as recreational drug [76]. Bendazac (42) is an indazole-containing oxyacetic acid drug that inhibits the denaturation of proteins [77] and is used for the treatment of joint and muscular pain [78]. This fused pyrazole derivative has the therapeutic potential to treat cataracts [79]. Tepoxalin (43) is a nonsteroidal anti-inflammatory drug and a dual inhibitor of cyclooxygenase and lipoxygenase approved in 1998 to treat osteoarthritic pain in animals [80,81]. This trisubstituted pyrazole derivative (43) contains a hydroxamic acid functional group [82]. Fomepizole (44, Antizole®) is an alcohol dehydrogenase inhibitor that has been approved to treat methanol or ethylene glycol poisoning [83,84] and is one of the smallest of the small-molecule drugs. In addition to the above-approved drugs, there are several pyrazole drugs such as lonazolac (nonsteroidal anti-inflammatory drug), romonabant (antiobesity), metamizole (pain relief), fezolamine (antidepressant), betazole (diagnostic agent), pyrazofurin (a rare pyrazole-containing natural product with antibacterial, anticancer and antiviral properties) and sulfaphenazole (antibacterial sulfonamide) that are in different stages of clinical trials or withdrawn from clinical use due to severe side effects. Several recent reviews can be consulted describing these obsolete or under clinical trial drugs [6–8].

Pyrazole derivatives as antibacterial agents

In addition to the numerous approved drugs discussed earlier, a large number of pyrazole derivatives are at different stages of preclinical development to treat different types of diseases. Several review articles have been published recently explaining the importance of the pyrazole nucleus in drug discovery. These compounds have α-glucosidase [85], carbonic anhydrase inhibitor [86], antineoplastic [87] and anti-inflammatory [88] properties, as well as several other therapeutic uses [89–91].

In our quest to find azole derivatives to be used as therapeutic agents [92–95], we have reported the various classes of pyrazole derivatives that can act as potent antibacterial agents [96–104], also summarized in our recent mini-review article [2]. In continuation of our research to discover novel antibacterial agents, we have found 1-[4-(trifluoromethyl)phenyl]pyrazole derivatives (44) to be potent methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE) agents with minimum inhibitory concentration (MIC) values less than 1 μg/ml (Figure 6). These compounds are effective against the biofilms of S. aureus, and persisters; metabolically inactive variant of the homogenous population of bacteria [105]. The corresponding hydrazone derivatives (45) of this class of compounds showed activity against Acinetobacter baumannii, in addition to MRSA and VRE bacteria, with an MIC value as low as 1.56 μg/ml [106]. A series of trifluoromethyl phenyl-substituted derivatives of pyrazole (46) has been found as potent antibacterial agents with selective activity against Gram-positive bacteria. These compounds (e.g., 46) are effective in inhibiting and eradicating the biofilms of S. aureus and Enterococcus faecalis at two-times the MIC value [107]. Similarly, we have found 3,5-bis(trifluoromethyl)phenyl-substituted pyrazole derivatives (e.g., 47) to be potent growth inhibitors of drug-resistant bacteria [108]. A number of in vitro mechanistic assays such as membrane permeability, scanning electron microscopy and CRISPRi studies have led the determination of these compounds as cell membrane-disrupting agents, most likely by inhibiting fatty acid biosynthesis [109]. Several reviews have been reported on the synthesis and therapeutic properties of pyrazole derivatives [6,85,86,110–113].

Figure 6. . Pyrazole derivatives as potent antibacterial agents.

Figure 6. 

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MIC: Minimum inhibitory concentration; MRSA: Methicillin-resistant Staphylococcus aureus; VRE: Vancomycin-resistant enterococci.

Conclusion

Pyrazole derivatives have been approved to treat different various diseases such as bacterial infections (cefoselis and ceftolozane), cancer (pirtobrutinib, futibatinib, asciminib, etc.), migraine (zavegepant), HIV (Lenacapavir), glaucoma (omidenepag), heart disease (vericiguat and umbralisib) and chronic graft-versus-host disease (belumosudil), as well as several other anomalies. Several pyrazole-derived drugs such as celecoxib and sildenafil have been among the most widely used medicines in the world. A myriad number of pyrazole derivatives are at different stages of preclinical and clinical development. Thus, based on these facts pyrazole is a privileged scaffold in drug discovery.

Future perspective

The pyrazole nucleus is the cornerstone of several approved drugs to treat different types of diseases. Recent approval of novel drugs has seen an uptick of this metabolically stable heterocycle. In many preclinical studies, it has been found that replacing other five-membered heterocycles with a pyrazole nucleus increases the antibacterial spectrum of the compounds. We can see more pyrazole derivatives among approved drugs and novel small compounds in the future. Metabolic stability of pyrazole derivatives is one of the important factors for its surge in newly approved drugs and novel compounds reported in literature.

Executive summary.

Introduction

  • Substituted pyrazole and fused-pyrazoles – 1H-indazole, 2H-indazole and pyrazolo[1,5-a]pyridine – are the common variants of this class of drugs.

  • Most the pyrazole-containing anticancer drugs are kinase inhibitors.

  • A myriad number of pyrazole derivatives are at different stages of clinical and preclinical trials.

Pyrazole-derived important drugs

  • Sildenafil is one of the blockbuster drugs that contains a fused-pyrazole moiety.

  • Zavegepant is one of the latest indazole-substituted drugs approved in 2023 to treat migraine.

  • Lenacapavir has been approved to treat multidrug-resistant HIV-1 infection. This unique drug has an extra-long half-life, which needs a dosing interval of 6 months.

  • Pralsetinib and selpercatinib have opened a new paradigm of RET precision oncology, which accounts for 2% of all cancers.

  • Baricitinib, a disubstituted pyrazole derivative, has been approved to treat several diseases such as alopecia, COVID-19, rheumatoid arthritis and Still's disease, an idiopathic systemic inflammatory disease of unknown etiology.

  • Larotrectinib is the first drug specifically approved to treat tumors based on their specific mutation rather than their origin.

Conclusion

  • The majority of pyrazole-containing drugs have been reported since 2016.

  • Pyrazole has emerged as an important heterocycle in drug discovery.

Supplementary Material

Click here for additional data file. (12.6KB, docx)

Footnotes

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.future-science.com/doi/suppl/10.4155/fmc-2023-0207

Financial disclosure

This review was made possible by Arkansas INBRE Research Grant supported by a grant from the National Institute of General Medical Sciences (NIGMS), P20 GM103429 from the NIH. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The author has no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as: • of interest; •• of considerable interest

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