CFG920,
Inhibitor Of Prostate Cancer With Fewer Cardiac Side Effects
Cas 1260006-20-9Novartis
Target: CYP17/CYP11B2
Disease: Castration-resistant prostate cancer
MF C14H13ClN4O
MW: 288.0778
Elemental Analysis: C, 58.24; H, 4.54; Cl, 12.28; N, 19.40; O, 5.54
Steroid 17-alpha-hydroxylase inhibitors
CFG920 is a CYP17 inhibitor, is also an orally available inhibitor of the steroid 17-alpha-hydroxylase/C17,20 lyase (CYP17A1 or CYP17), with potential antiandrogen and antineoplastic activities. Upon oral administration, CYP17 inhibitor CFG920 inhibits the enzymatic activity of CYP17A1 in both the testes and adrenal glands, thereby inhibiting androgen production. This may decrease androgen-dependent growth signaling and may inhibit cell proliferation of androgen-dependent tumor cells.
https://clinicaltrials.gov/ct2/show/NCT01647789
NCT01647789: A Study of Oral CFG920 in Patients With Castration Resistant Prostate Cancer2012
- 09 Nov 2015Adverse events, efficacy and pharmacokinetics data from the phase I part of a phase I/II trial in Prostate cancer (Metastatic disease) presented at the 27th AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (AACR-NCI-EORTC-2015)
- 29 Jan 2013Phase-I clinical trials in Prostate cancer in Spain (PO)
- 10 Dec 2012Phase-I clinical trials in Prostate cancer in Canada (PO)
Bethany Halford on Twitter: “CFG920 – @Novartis CMOS for …
twitter.com
Bethany Halford on Twitter: “CFG920 – @Novartis CMOS for castration resistant prostate cancer #ACSBoston MEDI 1st disclosures http://t.co/XJJ3tCvpUk”
Novartis is developing CFG-920 (structure shown), an oral
CYP17 inhibitor, for the potential treatment of metastatic
castration-resistant prostate cancer. In March 2013, a phase I/II trial
was initiated and at that time, the study was expected to complete in
January 2015; in August 2015, clinical data were presented
2015 250th (August 19) Abs MEDI 341
Discovery of CFG920, a dual CYP17/CYP11B2 inhibitor, for the treatment of castration resistant prostate cancer
American Chemical Society National Meeting and Exposition
Christoph Gaul, Prakash Mistry, Henrik Moebitz, Mark Perrone, Bjoern Gruenenfelder, Nelson Guerreiro, Wolfgang Hackl, Peter Wessels, Estelle Berger, Mark Bock, Saumitra Sengupta, Venkateshwar Rao, Murali Ramachandra, Thomas Antony, Kishore Narayanan, Samiulla Dodheri, Aravind Basavaraju, Shekar Chelur
2015 250th (August 19) Abs MEDI 341
Discovery of CFG920, a dual CYP17/CYP11B2 inhibitor, for the treatment of castration resistant prostate cancer
American Chemical Society National Meeting and Exposition
Christoph Gaul, Prakash Mistry, Henrik Moebitz, Mark Perrone, Bjoern Gruenenfelder, Nelson Guerreiro, Wolfgang Hackl, Peter Wessels, Estelle Berger, Mark Bock, Saumitra Sengupta, Venkateshwar Rao, Murali Ramachandra, Thomas Antony, Kishore Narayanan, Samiulla Dodheri, Aravind Basavaraju, Shekar Chelur
CHEMISTRY COLLABORATORS
Novartis-Aurigene team: (from left) Brahma Reddy V,
Thomas Antony, Murali Ramachandra, Venkateshwar Rao G, Wesley Roy
Balasubramanian, Kishore Narayanan, Samiulla DS, Aravind AB, and Shekar
Chelur. Not pictured: Björn Grünenfelder, Saumitra Sengupta, Nelson
Guerreiro, Andrea Gerken, Mark Perrone, Mark Bock, Wolfgang Hackl,
Henrik Möbitz, Peter Wessels, Christoph Gaul, Prakash Mistry, and
Estelle Marrer.
Credit: Aurigene
Aurigene Discovery Technologies Limited, an independent subsidiary of Dr Reddy’s, CSN Murthy is chief executive officer |
Preclinical and clinical studies were performed to evaluate the efficacy of CFG-920,
a dual cytochrome P450 (CYP)17 and CYP11B2 dual inhibitor, for the
potential treatment of castration resistant prostate cancer. CFG-920
showed potent activity against human CYP17 and CYP11B2 enzymes with IC50
values of 0.023 and 0.034 microM, respectively. In monkeys, treatment
with CFG-920 (3 mg/kg, po) showed good bioavailability (93%), Tmax of
0.5 h, Cmax of 1382 nM.dn and AUC of 2364 nM.h, while CFG-920 (10 mg/kg,
po) showed F value of 183%, Cmax of 1179 nM.dn and Tmax of 1.04 h. In a
phase I, first-in-man study, patients received continuous po dosing of
CFG-920 (50 mg, bid) plus prednisone (5 mg) in 28-day cycles. At the
time of presentation, CFG-920 was under phase II development.
CFG920
WO 2010149755
Novartis team: (clockwise from left) Wolfgang Hackl,
Henrik Möbitz, Peter Wessels, Christoph Gaul, Prakash Mistry, and
Estelle Marrer., Credit: Novartis
Prostate cancer is the most commonly occurring cancer in men. Doctors
often treat the metastatic stage of the disease by depriving the
patient of sex hormones via chemical or surgical castration. But if it
progresses far enough, the cancer can survive this therapy, transforming
into the castration-resistant form. “Once the cancer becomes
castration-resistant, the prognosis is poor,” said Novartis’s Christoph Gaul.
In recent years, CYP17, a bifunctional 17α-hydroxylase/17,20-lyase
cytochrome P450 enzyme, has emerged as a target for treating
castration-resistant prostate cancer. The enzyme catalyzes the
biosynthesis of sex hormones, including testosterone, and blocking it
can starve prostate cancer of the androgens it needs to thrive.
Johnson & Johnson’s CYP17 inhibitor, abiraterone acetate
(Zytiga), a steroid that binds irreversibly to CYP17, was approved by
the Food & Drug Administration in 2011. But Novartis scientists
thought they could make a better CYP17 inhibitor, Gaul told C&EN.
They teamed up with researchers at Aurigene, in Bangalore, India, and came up with their clinical candidate, CFG920.
Unlike abiraterone, CFG920 isn’t a steroid, and it inhibits CYP17
reversibly. It also reversibly inhibits another cytochrome P450 enzyme,
CYP11B2, which is involved in the synthesis of the mineralocorticoids,
hormones that regulate cardiac function.
Treating prostate cancer patients by lowering their androgen levels
turns out to have negative cardiac side effects: Patients’ lipid
metabolism is thrown off and their mineralocorticoid levels jump,
leading to increases in blood pressure. Those changes can be stressful
for the heart. “If prostate cancer patients don’t die because of the
cancer, a lot of times they die because of cardiac disease,” Gaul said.
Because CFG920 also keeps mineralocorticoid levels in check, Novartis
is hoping the drug candidate will ameliorate some of the cardiac side
effects of inhibiting CYP17. The compound is currently in Phase I
clinical trials.
PATENT
WO 2010149755
https://www.google.co.in/patents/WO2010149755A1?cl=en
Example 58PATENT
WO 2010149755
https://www.google.co.in/patents/WO2010149755A1?cl=en
Prύpιn”ation ofI'(2’ChIoroψ}ri(ibi-^’\l)’3’f4’metMψ}τUin’3’yl)-imiJazoliJin’2’θne (5HA)-
Using the same reaction conditions as in Example 14. 1-(4-methyl-pyridin-3-yl)- itnida/olidin-2-onc ().-.!.4b: 600 mg. 3.3898 mmol) uas reacted with 2-chloro-4-iodo- py.idine (974 mg.4.067 mmol). 1 , 4-dioxane (60 mL). copper iodide (65 mg, 0.3398 mmol), /r<w.v-1.2-diamino cycK)hexane (0.12 ml,, 1.0169 mmol) and potassium phosphate (2.15 g, 10.1694 mmol) to afford 810 mg of the product (83% yield).
1H NMR (C1DCI3. 300 Mi l/): 6 8.5-8.4 (m. 211). 8.3 (d. IH), 7.6-7.5 (m, 2H). 7.2 (S. 111). 4.1-3.9 (ni. 4H), 2.35 <s. 3H)
LCVIS puιϊt>: 90.8%. nι-7 – 289.1 (M M)
HPl C: 97.14%
REFERENCES
1: Gomez L, Kovac JR, Lamb DJ. CYP17A1 inhibitors in castration-resistant prostate cancer. Steroids. 2015 Mar;95:80-7. doi: 10.1016/j.steroids.2014.12.021. Epub 2015 Jan 3. Review. PubMed PMID: 25560485; PubMed Central PMCID: PMC4323677.
2: Yin L, Hu Q, Hartmann RW. Recent progress in pharmaceutical therapies for castration-resistant prostate cancer. Int J Mol Sci. 2013 Jul 4;14(7):13958-78. doi: 10.3390/ijms140713958. Review. PubMed PMID: 23880851; PubMed Central PMCID: PMC3742227.
///////CFG-920, CYP17 inhibitor (prostate cancer), Novartis, CFG 920, Novartis scientists, team up , researchers , Aurigene, Bangalore, India,