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Rapalogs Potential as Practical Alternatives to Rapamycin Ahmed F. Abdel-Magid* Therachem Research Medilab, LLC., 100 Jade Park, Chelsea, Alabama 35043, United States
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Important Compound Classes.
and antifungal agent. It can prevent and/or treat diseases and conditions such as insulin-dependent diabetes mellitus, psoriasis, smooth muscle cell proliferation, and intimal thickening following vascular injury, adult T-cell leukemia, malignant carcinomas, cardiac inflammatory disease, and others. However, rapamycin displays very low and variable oral bioavailability, which limits its therapeutic use. In addition, it is difficult to formulate to obtain stable galenic compositions. To overcome these disadvantages, many researchers have modified the structure of rapamycin to prepare numerous analogues (known commonly as rapalogs) attempting to improve pharmacological properties. Examples include the preparation of water-soluble prodrug esters at C28 and C40, formation of acetal analogues, silyl ethers, and hydroxy esters as well as aryl, alkyl, alkenyl, and alkynyl analogues. Many modifications have targeted one or more of methoxy, hydroxy, and keto groups. Other modifications targeted the 6-membered pipecolate (piperidine-2-carboxylate) ring and the cyclohexane ring. Researchers have synthesized a wide variety of novel rapalogs with improved pharmacologic profiles and stability with the hope that they can be useful alternatives for rapamycin to treat diseases such as cancer and neurodegenerative disorders while eliminating undesired immunosuppressive side effects of rapamycin. The mammalian target of rapamycin (mTOR) kinase is a member of the phosphatidylinositol 3-kinase-related kinase family of serine/threonine protein kinases. mTOR has other names including “the mechanistic target of rapamycin” and “FK506-binding protein 12-rapamycin-associated protein 1” (FRAP1). It exists in two distinct multiprotein complexes, mTORC1 and mTORC2. mTORC1 is a key regulator of protein translation and autophagy. It can integrate signals from growth factors and nutrients and controls cell growth and metabolism. Rapamycin and rapalogs are allosteric inhibitors of mTORC1 complex. FK506 (also known as tacrolimus) is an immunosuppressive drug. FK506 binding proteins (FKBPs) are a family of highly conserved proteins in eukaryotes. Rapamycin (or any rapalog) functions through the formation of intracellular complexes with one of three FKBP proteins: FKBP12, FKBP51, or FKBP52. The resulting FKBP−rapamycin complex then binds to the FK506−rapamycin binding (FRB) domain of mTOR causing the allosteric inhibition of mTORC1 kinase. mTORC1 activity is linked to both benign and malignant proliferation disorders; therefore, rapamycin and rapalogs have gained clinical importance for cancer treatment because of their abilities to inhibit mTORC1.
Title. Rapamycin Derivatives Patent Application Number. WO 2019/064182 A1 Publication Date. April 4, 2019 Priority Application. US 62/563,312 Priority Date. September 26, 2017 Inventors. Bonazzi, S.; Connolly, M.; Glass, D. J.; Mihalic, M.; Patterson, A. W.; Roggo, S.; Shavlakadze, T. Assignee Company. Novartis AG; Lichtstrasse 35, 4056 Basel, Switzerland Disease Area. Cancer, neurodegenerative disorders, transplant rejection, autoimmune diseases, inflammation, fungal infections, age-related diseases, and many others Biological Target. Mammalian target of rapamycin (mTOR) kinase Summary. The invention in this patent application relates to modified rapamycin analogues represented generally by formula I. These compounds are inhibitors of mTORC1 and may potentially be useful in the treatment of a wide variety of diseases or disorders including but not limited to cancer, neurodegenerative disorders, transplant rejection, autoimmune diseases, inflammation, fungal infections, age-related diseases, and many others. Rapamycin or sirolimus (structure above) is a macrolide molecule produced by Streptomyces hygoscopius. It possesses activities as a potent immunosuppressant, antibiotic, antitumor, © XXXX American Chemical Society
Received: May 13, 2019
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DOI: 10.1021/acsmedchemlett.9b00215 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
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Key Structures. The inventors described the structures and synthesis of 18 examples of formula I including the following representative examples. Modifications of rapamycin at C16, C32, and C40 are highlighted in blue. These compounds are pure isomers; the wiggly bond at C16 in some structures indicates absolute stereochemistry was not assigned.
Aging is regulated in nonmammals by signaling pathways such as the TOR (the nonmammalian equivalent of mTOR) pathway and in mammals by mTORC1 pathway. Animal studies showed that inhibition of TOR or mTORC1 signaling extended lifespan and delayed the onset of age-related diseases in many organisms, ranging from flies to mammals. Studies included inhibition of the TOR pathway by genetic mutation to extend lifespan of yeast, C. elegans, and drosophila and use of the mTORC1 inhibitors to prolong lifespan of mice. Noticeably, rapamycin extended the lifespan of mice even when administered late in life. A clinical trial on elderly men determined that inhibition of mTOR with rapamycin improved their immune function. These data raised the possibility that drugs targeting mTOR pathway may provide desirable therapeutic effects on aging and agerelated diseases in humans. However, in spite of these encouraging results, investigators remain cautious of using currently available mTOR inhibitors in human aging trials due to their undesirable side effects such as immunosuppression, cytopenia, stomatitis, GI distress, and interstitial pneumonitis. Thus, finding new inhibitors without the undesirable side effects would be beneficial. Focal cortical dysplasia (FCD) is an abnormality of cortical development. It is a common cause of refractory epilepsy in children and medically intractable seizures in adults. Tuberous sclerosis complex (TSC) genes, TSC1 and TSC2, control cell growth by inhibiting mTOR. Mutations in these genes lead to the development of the TSC disease, which is considered a type of FCD and has been characterized by formation of benign tumors, mental retardation, and high incidences of epilepsy. Animal and human studies have implicated the mTOR pathway in mediating the cellular and molecular changes leading to cortical malformations and the expression of epilepsy. Aberrant activation of mTOR interferes with normal brain development and causes epilepsy. Studies using TSC and PTEN mouse models demonstrated that treatment with rapamycin decreases structural abnormalities and reduces seizure occurrences. Inhibition of the mTOR pathway in an acquired epilepsy model, either before or immediately after neurological insults, has been shown to prevent pathological changes in animal brains and development of spontaneous recurrent seizure. Therefore, the use of rapamycin and rapalogs may potentially be a viable treatment for TSC and related disorders. Mitochondrial myopathy (MM) is a disease that causes prominent muscular problems. The disease induces integrated mitochondrial stress response (ISRmt), which is controlled by mTORC1 in skeletal muscle. The inhibition of mTORC1 by rapamycin downregulated all components of ISRmt, improved all MM symptoms, and reversed the progression of even late stage MM without inducing mitochondrial biogenesis. Therefore, rapamycin and rapalogs may also provide a treatment for MM. The therapeutic potential of rapamycin and rapalogs for the treatment of these many diseases emphasizes the importance of introducing new rapalogs with improved mTORC1 inhibitory activity, good oral bioavailability, sufficient metabolic stability, and favorable pharmacokinetic properties. It is also desirable to obtain stable nonhygroscopic solid inhibitors for easy formulation. The rapalogs described in this patent application were obtained by modification of rapamycin at C16, C32, and C40. These compounds are inhibitors of mTORC1 and possess some of the desired properties and may potentially be used as practical alternatives to rapamycin in treating many diseases and disorders, vide supra.
Biological Assay. • Cell-based assay for rapalog potency determination. • SPR assay to determine binding affinity to FK506-binding proteins (FKBP). Biological Data. The biological data obtained from testing rapamycin and the above representative examples from the potency assay are listed in the table:
Recent Review Articles. 1) Waldner, M.; Fantus, D.; Solari, M.; Thomson, A. W. Br. J. Clin. Pharmacol. 2016, 82 (5), 1158−1170. 2) Fouqué, A.; Jean, M.; van de Weghe, P.; Legembre, P. Recent Pat. Anti-Cancer Drug Discovery 2016, 11 (3), 283− 296. 3) Meng, L.-H.; Zheng, X. F. S. Acta Pharmacol. Sin. 2015, 36 (10), 1163−1169. B
DOI: 10.1021/acsmedchemlett.9b00215 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
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The author declares no competing financial interest.
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DOI: 10.1021/acsmedchemlett.9b00215 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
