Novel 3-Aryl Indoles as Progesterone Receptor Antagonists for Uterine Fibroids

Abstract

We report the synthesis and characterization of novel 3-aryl indoles as potent and efficacious progesterone receptor (PR) antagonists with potential for the treatment of uterine fibroids. These compounds demonstrated excellent selectivity over other steroid nuclear hormone receptors such as the mineralocorticoid receptor (MR). They were prepared from 2-bromo-6-nitro indole in four to six steps using a Suzuki cross-coupling as the key step. Compound 8f was orally active in the complement 3 model of progesterone antagonism in the rat uterus and demonstrated partial antagonism in the McPhail model of progesterone activity.KEYWORDS Progesterone, progesterone receptor, NR3C3, progesterone receptor antagonist, uterine fibroids, Suzuki cross-coupling reaction U terine fibroids (leiomyomas) are benign tumors that develop from smooth muscle cells and fibrous connective tissues of the uterus. 1-3 Although most are asymptomatic, in some women fibroids cause abnormal menstrual bleeding, pelvic pain, and reproductive dysfunction. 4 The incidence of fibroids increases with age during the reproductive years and peaks between 35 and 40 years old. 5 For those women whose quality of life is negatively impacted, hysterectomy is often necessary. As a result, fibroids are the primary indication for over 200,000 hysterectomies in the U.S. per year. 6,7 An evaluation of hysterectomy cases revealed a similar incidence (77%) in both post-and premenopausal women. 8 The fertility of premenopausal women can be decreased by the presence of submucosal myomas, which are fibroids partially in the cavity and partially in the wall of the uterus. 9 Since hysterectomy is unacceptable for a woman who desires a future pregnancy, surgical procedures have been developed that preserve the uterus, such as myomectomy (fibroid removal with uterine retention), laser ablation, or embolization. Removal of fibroid growths can restore fertility. 9 However, these treatments are invasive, expensive, and associated with a high rate of fibroid recurrence. 10 Therefore, there is an unmet medical need for a noninvasive, pharmaceutical treatment of uterine fibroids in both post-and premenopausal women.Currently the only pharmaceutical treatment for uterine fibroids involves the use of gonadotropin-releasing hormone (GnRH) agonists such as Lupron. These peptide hormones act on the pituitary gland, resulting in a down-regulation of the hypothalamic-pituitary-ovarian (HPO) axis, which decreases the release of gonadotropins (FSH and LH) and subsequently reduces the production of the ovarian hormones estrogen and progesterone. Withdrawal of ovarian hormone stimulation reduces uterine volume and fibroid size. 11 Unfortunately, this benefit is accompanied by side effects, most notably bone loss, which limits treatment duration. Once therapy is discontinued, fibroids usually return. As a result, GnRH agonists are primarily used to reduce fibroid size prior to surgical removal.Clinically, fibroids enlarge in women treated with norethynodrel, a steroidal progesterone ...

Transition‐Metal‐Free C3 Arylation of Indoles with Aryl Halides

“…For instance, fluvastatin is an FDA-approved HMG-CoA reductase inhibitor that is used in the clinic for lowering LDL cholesterol. [1] Other C3 arylated indoles exhibit pico-to nanomolar inhibitory actions against a wide range of biological targets and processes such as the progesterone receptor, [2] COX-II enzyme, [3] carbonic anhydrase I and II, [4] and tubulin polymerization, [5] etc.…”

“…[2,[6][7][8][9][10][11][12][13][14] Methods utilizing C-H activation have also been reported. [15][16][17][18] While transition metal-free Correspondence to: Jimmy Wu.…”

“…For instance, fluvastatin is an FDA-approved HMG-CoA reductase inhibitor that is used in the clinic for lowering LDL cholesterol. [1] Other C3 arylated indoles exhibit pico-to nanomolar inhibitory actions against a wide range of biological targets and processes such as the progesterone receptor, [2] COX-II enzyme, [3] carbonic anhydrase I and II, [4] and tubulin polymerization, [5] etc.The direct introduction of aromatic groups onto an extant indole nucleus at C3 is typically carried out by transition metal-catalyzed cross-coupling reactions (Figure 1). [2,[6][7][8][9][10][11][12][13][14] Methods utilizing C-H activation have also been reported.…”

“…A brief solvent survey identified DMF and DMSO as the only effective solvents (entries [1][2][3][4][5]. A reaction performed in the dark resulted in similar yield and selectivity (entry 7 vs 5).…”

Metal Catalyzed Suzuki-Miyaura Cross-Coupling– Efficient Methodology for Synthesis the Natural and non-Natural biological active Molecules

“…These analogs were also prepared by adopting Suzuki cross coupling reaction as a key step from 2-bromo-6-nitro indole (6) (Scheme 3) [6]. Thiophenes derivaties are valuable building blocks for many natural and non-natural products and show potential applications in the flavour and pharmaceutical industries along with materials science.…”