FDA approved the marketing of 14 drugs in the third quarter of 2023, including 6 small molecule drugs. This article mainly focuses on the drug design ideas of small molecule drugs, hoping to provide design inspiration to the majority of researchers in the field of small molecule drugs.
Vanflyta (Quizartinib)
Basic Information of Quizartinib
Quizartinib is a second-generation small molecule inhibitor of FLT3 kinase developed by Daiichi Sankyo in Japan for the treatment of adult patients with acute myeloid leukemia (AML) with FLT3-ITD mutations. Quizartinib and its primary active metabolite, AC886 (methyl to hydroxymethyl), bind with low nM affinity to the ATP pocket of FLT3 and are 10-fold more active against FLT3-ITD mutants than wt FLT3. First-generation FLT3 small-molecule inhibitors have been marketed previously, but most of them are generally selective for the FLT3 kinase.
In the U.S., 20,380 new AML patients are expected to be diagnosed in 2023, with up to 37% of newly diagnosed AML having FLT3 mutations (approximately 80% are FLT3-ITD mutations). These mutations will often lead to an unfavorable prognosis, including an increased risk of recurrence and a shorter overall survival. The five-year survival rate for FLT3-ITD AML patients has been reported to be approximately 20%.
Idea of Molecular Design
A small kinase-centered library was first analyzed by KinomeScan to obtain a diarylurea backbone, and a simple benzene ring substituent SAR yielded the highly active and selective (Kd = 1.6 nM) lead molecule AB530. However, the aqueous solubility and oral PK of AB530 at higher doses need to be optimized. Introduction of solubilizing group and removal of amide linker gave the marketed drug Quizartinib.
Xdemvy (Lotilaner)
Basic Information of Lotilaner
Lotilaner is an ectoparasiticide eye drop developed by Tarsus Pharma for the treatment of helminthic mite blepharitis. Lotilaner is an ectoparasiticidal eye drop developed by Tarsus Pharma for the treatment of demodex blepharitis. lotilaner is a γ-aminobutyric acid (GABA)-gated chloride channel inhibitor that is highly selective against mites, causing a paralyzing effect and eventual death of the target organism. Lotilaner has excellent selectivity and does not inhibit GABA chloride channels in mammals. Lotilaner was previously marketed as an antiparasitic veterinary drug (insecticide).
Demodex blepharitis is caused by infection by demodex, the most common ectoparasite on human skin. There are about 25 million patients in the United States.
Idea of Molecular Design
Lotilaner was apparently obtained by simple optimization from previously reported insecticides.
Zurzuvae (Zuranolone)
Basic Information of Zuranolone
Zuranolone is a steroidal orthoallosteric modulator of the neuroactive γ-aminobutyric acid A receptor (GABA-A) co-developed by Sage Therapeutics and Biogen for the treatment of postpartum depression (PPD) in adults. Zuranolone is the first oral medication used to treat postpartum depression in adults. Postpartum depression is one of the most common complications during and after pregnancy. It is estimated that 1 in 8 women will experience symptoms of postpartum depression. Without proper screening, perhaps half of PPD cases is undiagnosed and only 15.8% of female patients receive treatment.
Idea of Molecular Design
Zuranolone was developed as an improvement on the intravenous neurosteroid brexanolone (also known as Allopregnanolone, an endogenous neurosteroid) by removing C-19, introducing pyrazole, and cyanide suctioning electron, which increased oral bioavailability and penetration into the brain and significantly improved PK. Zuranolone has a biological half-life suitable for once-daily administration (approximately 16-23 hours), whereas brexanolone has a half-life of approximately 9 hours.
Sohonos (Palovarotene)
Basic Information of Palovarotene
Palovarotene is an orally bioavailable retinoic acid receptor gamma (RAR-γ) receptor agonist developed by Ipsen to reduce the volume of new heterotopic ossification in patients with FOP (Fibrodysplasia Ossificans Progressiva, commonly known as “stoner’s disease”). Abnormal bone formation in patients with FOP is driven by functionally acquired mutations in the bone morphogenetic protein (BMP) type I receptor ALK2. Sohonos has specific selectivity for RAR-γ. By binding to RAR-γ, Palovarotene inhibits SMAD1/5/8 phosphorylation to reduce the BMP/ALK2 downstream signaling pathway, thereby reducing ALK2/SMAD-dependent chondrogenesis and osteoblast differentiation. Fibrodysplasia Ossificans Progressiva is a rare autosomal dominant disorder with only about 900 patients worldwide. The patient’s connective tissues, such as muscles, tendons, and ligaments, gradually transform into bone tissue, resulting in restricted movement, deformity, and severe disability. Sohonos was first developed by Roche for the treatment of COPD emphysema. It has been rejected three times previously by the FDA and EMA combined.
Idea of Molecular Design
No drug discovery articles found for palovarotene. However, the author found that the pan-RAR agonists TTNPB and palovarotene are structurally similar and are both conformationally restricted analogues of retinoic acid. Palovarotene is supposed to be obtained by optimizing the RAR-γ selectivity on the basis of the structure of TTNPB.
Ojjaara (Momelotinib)
Basic Information of Momelotinib
Momelotinib is an oral JAK1/JAK2, ACVR1 inhibitor developed by GSK for the treatment of intermediate to high risk myelofibrosis, and is the only drug used in newly diagnosed and previously treated myelofibrosis. Myelofibrosis is a rare hematological neoplasm caused by dysregulation of the JAK signal transducer and activator of transcriptional protein signaling, characterized by systemic symptoms, splenomegaly, and progressive anemia. Myelofibrosis affects approximately 25,000 patients in the United States.
Idea of Molecular Design
Screening of Cytopia’s internal library of kinase compounds against the isolated JAK2 enzyme and a JAK2-dependent engineered cell line (Baf3TEL-JAK2) identified several hit submicromolar N -(4-morpholino-phenyl)-4-arylpyrimidin-2-amines. Although there is a docking structure, it doesn’t involve much SBDD based on the optimization ideas in the article, and is more of a SAR based on medicinal chemistry experience. Researchers performed SAR on substituents of pyrimidine to optimize activity and oral utilization to obtain Momelotinib.
Approved JNK Inhibitors at BOC Sciences
| CAS | Name | Description |
| 941678-49-5 | Ruxolitinib | Ruxolitinib is a potent and selective JAK1/2 inhibitor. |
| 477600-75-2 | Tofacitinib | Tofacitinib is an orally available JAK3 inhibitor |
| 1187594-09-7 | Baricitinib | Baricitinib is a selective and orally bioactive inhibitor of JAK1 and JAK2. |
| 1310726-60-3 | Upadacitinib | Upadacitinib is a selective JAK inhibitor. |
| 936091-26-8 | Fedratinib | Fedratinib is a potent and selective JAK2 inhibitor with IC50 value of 6 nM. |
| 1622902-68-4 | Abrocitinib | Abrocitinib is a seletive JAK1 inhibitor with IC50 value of 29 nM. |
| 1792180-81-4 | Ritlecitinib | Ritlecitinib is a selective JAK3 inhibitor with IC50 value of 0.346 nM. |
Exxua (Gepirone)
Basic Information of Gepirone
Gepirone is a first-in-class oral 5HT1A receptor selective agonist developed by Fabre-Kramer for the treatment of major depressive disorder (MDD) in adults. The antidepressant mechanism of Gepirone is thought to be related to its 5HT1A receptor-selective agonist activity. The drug was submitted to the FDA in 2004, 2007, and 2015, but was not approved due to lack of substantial evidence of effectiveness. Prior to COVID-19, more than 20 million adults in the United States experienced major depression each year.
Idea of Molecular Design
Gepirone was first developed by BMS in 1986 and is a structural analog of the 1986 marketed drug Buspirone (buspirone), which is also in the Azapirone drug class. However, Buspirone is an Gepirone is a selective agonist at the 5HT1A receptor used for the treatment of major depressive disorder in adults. Buspirone has a shorter half-life (2-3 hours) and therefore requires BID or TID administration, whereas Gepirone has an oral bioavailability of 14-17% and requires only once daily administration. The active metabolite of both is 1-pyrimidinylpiperazine (1-PP), an α2 receptor antagonist.
References
- https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2023
- J. Med. Chem. 2009, 52, 7808–7816
- Bioorganic & Medicinal Chemistry 2021, 30, 115934
- J. Med. Chem. 2017, 60, 7810–7819
- Nat. Med. 2011, 17, 454–460.
- Bioorg. Med. Chem. Lett. 2009, 19, 5887-5892.