Development of Selective Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 for the Treatment of Endometriosis


Endometriosis affects 5-10% of the female population. Due to the difficult diagnosis of this disease, the percentage of unreported cases is probably larger. Present therapies with GnRH agonists and anti-estrogens aim to reduce the estrogen activity. Their main disadvantage is the rather rigourous, non-selective reduction of estrogen levels throughout the body, often leading to severe (postmenopausal-like) side-effects like osteoporosis.
Local production of estradiol (E2) plays a pivotal role in endometriosis and continuously high E2 concentrations are found in peritoneal and ovarian endometriotic tissue (1). Thus, tissue-selective reduction of endometriotic levels of E2 should result in much less side-effects than observed in the established therapies
in vivo pharmacokinetic profiles of the compounds are determined prior to proof of principle studies in an in vivo endometriosis mouse model.

References

  1. Huhtinen K, Desai R, Ståhle M, Salminen A, Handelsman DJ, Perheentupa A, Poutanen M (2012) Endometrial and Endometriotic Concentrations of Estrone and Estradiol Are Determined by Local Metabolism Rather than Circulating Levels. J Clin Endocrinol Metab doi: 10.1210/jc.2012-1154
  2. Oster A, Hinsberger S, Werth R, Marchais-Oberwinkler S, Frotscher M, Hartmann RW ββ-HSD1) for the treatment of estrogen-dependent diseases. J Med Chem 53, 8176-8186
  3. Henn C, Einspanier A, Marchais-Oberwinkler S, Frotscher M, Hartmann RW (2012) Lead optimization of 17β-HSD1 inhibitors of the (hydroxyphenyl)naphthol sulfonamide type for the treatment of endometriosis. J Med Chem 55, 3307-3318
  4. Bey E, Marchais-Oberwinkler S, Negri M, Kruchten P, Oster A, Klein T, Spadaro A, Werth R, Frotscher M, Birk B, Hartmann RW (2009) New insights into the SAR and binding modes of bis(hydroxyphenyl)thiophenes and -benzenes: influence of additional substituents on 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitory activity and selectivity. J Med Chem 52, 6724-6743

 

 


Estrogen deficiency is believed to be responsible for the rapid progression of osteoporosis. High prevalence of this disease is observed in women after the menopause when serum estrogen levels drop. On the other hand, the osteoprotective action of estrogens is well- known: estrogens control bone remodeling during reproductive life in both women and men and they inhibit osteoclastogenesis leading to a decrease in bone resorption. Furthermore, there is substantial evidence that potent androgens like testosterone and dihydrotestosterone are involved in bone formation and might protect bone from osteoporosis. 
for the treatment of osteoporosis (1, 2, 3). Indeed, this approach has recently been validated in an in vivo
in vivo

  1. Xu K, Al-Soud YA, Wetzel M, Hartmann RW, Marchais-Oberwinkler SEur J Med Chem. 46, 5978-5990
  2. Wetzel M, Marchais-Oberwinkler S, Perspicace E, Möller G, Adamski J, Hartmann RWJ Med Chem. 54, 7547-7557
  3. Wetzel M, Gargano EM, Hinsberger S, Marchais-Oberwinkler S, Hartmann RWEur J Med Chem. 47, 1-17

 

 




The absence of effective and safe therapy for high cortisol levels has encouraged us to design novel CYP11B1 inhibitors that are more potent and selective. We have developed non-steroidal CYP11B1 inhibitors that show IC50 values in the low nanomolar range with significantly higher selectivity over CYP11B2 than metyrapone, and do not inhibit CYP17 and CYP19 (aromatase) (1, 2). These CYP11B1 inhibitors demonstrate an acceptable metabolic stability profile. Currently, proof of principle studies with our CYP11B1 inhibitors are being performed for the different disease indications.

References

  1. Hille UE, Zimmer C, Vock CA, Hartmannn RW (2011) First selective Cyp11b1 inhibitors for the treatment of cortisol-dependent diseases. ACS Med Chem Lett 2, 2-6
  2. Yin L, Lucas S, Maurer F, Kazmaier U, Hu Q, Hartmann RW (2012) Novel imidazol-1-ylmethyl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-ones as potent and selective CYP11B1 inhibitors for the treatment of Cushing's syndrome.  J Med Chem 55, 6629-6633

 

 

Development of Inhibitors of Aldosterone Synthase (CYP11B2)


In industrialized nations, cardiovascular diseases remain the main cause of death for both men and women among all racial and ethnic groups. Chronic elevations in plasma aldosterone levels have been diagnosed in a variety of diseases such as congestive heart failure and certain forms of high blood pressure. Present therapies with steroidal aldosterone antagonists reduce pathological levels of disease-associated aldosterone, thereby reducing the general risk of certain cardiovascular diseases. However, the use of steroidal aldosterone antagonists is accompained by serious side effects due to their interaction with other steroidal receptors. We identified CYP11B2 as a novel target for a new therapeutic approach of congestive heart failure, myocardial fibrosis and hyperaldosteronism. The biosynthesis of aldosterone, the most potent of all mineralcorticoids, is catalized by the aldosterone synthase CYP11B2. The targeted inhibition of CYP11B2 by highly specific non-steroidal inhibitors designed by ElexoPharm reduces pathological levels of disease-associated aldosterone, thereby reducing the general risk of certain cardiovascular diseases. Due to the non-steroidal structure of these inhibitors no side effects in the endocrine system are expected.

  

EUROSTARS program MITOTREAT - E!6654 targeting mitochondrial diseases


ElexoPharm is collaborating with Khondrion BV (Nijmegen), Radboud University Nijmegen Medical Centre (RUNMC, Nijmegen) and Pharmacelsus GmbH (Saarbrücken) to discover treatments for mitochondrial diseases with high unmet medical need (approximately 300,000 patients in industrialized countries).

Development of Angiogenesis Inhibitors for the treatment of Colorectal Cancer


in silico modeling, state-of the-art chemical synthesis and Surface Plasmon Resonance (SPR) technologies.


The project is a collaboration of ElexoPharm GmbH with Argon Pharma SL (Spain), Admescope Ltd. (Finland), PharmBioTec GmbH and Pharmacelsus GmbH (both in Germany). This grant is awarded for a period of three years and will allow the development of low molecular weight inhibitors of focal adhesion signaling for the treatment of various cancers. Inhibition of focal adhesion signaling induces apoptosis in cancer cell lines, while having virtually no effect on healthy cells. As a consequence, inhibition of focal adhesion signaling provides a novel and highly promising tumor-selective mechanism of action in cancer therapy. This project is financially supported by the German Federal Ministry of Education and Research (Projektträger Jülich). At ElexoPharm, lead finding and lead optimization based on molecular modelling, design of biological active compounds and their synthesis will be performed.