RESUMO
Sex steroid receptors are ligand-triggered transcription factors. Oestrogen, progesterone and androgen receptors form, together with the glucocorticoid and mineralocorticoid receptors, a subgroup of the superfamily of nuclear receptors. They share a common mode of action, namely translating a hormone-i.e. a small-molecule signal-from outside to changes in gene expression and cell fate, and thereby represent "natural" pharmacological targets.For pharmacological therapy, these receptors have originally been addressed by hormones and synthetic hormone analogues in order to overcome pathologies related to deficiencies in the natural ligands. Another major use for female sex hormone receptor modulators is oral contraception, i.e. birth control.On the other side, blocking the activity of sex steroid receptors has become an established way to treat hormone-dependent malignancies, such as breast and prostate cancer.In this review, we will discuss how the experience gained from the classical pharmacology of these receptors and their molecular similarities led to new options for the treatment of gender-specific diseases and highlight recent progress in medicinal chemistry of sex hormone-modulating drugs.
Assuntos
Antagonistas de Hormônios/uso terapêutico , Receptores Androgênicos/efeitos dos fármacos , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Progesterona/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/fisiologia , Receptores de Estrogênio/fisiologia , Receptores de Progesterona/fisiologia , Moduladores Seletivos de Receptor Estrogênico/uso terapêuticoRESUMO
Herein we describe the chemical synthesis and pharmacological characterization of a novel, highly potent progesterone receptor (PR) antagonist, ZK 230211. The introduction of a 17alpha-pentafluorethyl side chain in the D-ring of the steroid skeleton allowed the combination of high antiprogestagenic activity with little or no other endocrinological effects. In contrast to many other antiprogestins, ZK 230211 did not convert to an agonist in the presence of protein kinase A (PKA) activators and showed high antiprogestagenic activity on both PR isoforms PR-A and PR-B. This high antiprogestagenic activity could also be demonstrated in several in vivo models. Furthermore, this compound displayed only marginal antiglucocorticoid effects. In tumor models ZK 230211 exhibited strong antiproliferative action. The pharmacological properties of ZK 230211 may prove useful in the treatment of endometriosis, leiomyomas, breast cancer, and in hormone replacement therapy.
Assuntos
Estrenos/síntese química , Antagonistas de Hormônios/síntese química , Receptores de Progesterona/antagonistas & inibidores , Abortivos/síntese química , Abortivos/metabolismo , Abortivos/farmacologia , Adrenalectomia , Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/metabolismo , Antagonistas de Androgênios/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Ligação Competitiva , Castração , Linhagem Celular , Estrenos/metabolismo , Estrenos/farmacologia , Feminino , Glucocorticoides/antagonistas & inibidores , Gonanos/farmacologia , Antagonistas de Hormônios/metabolismo , Antagonistas de Hormônios/farmacologia , Ligantes , Masculino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Mifepristona/farmacologia , Progesterona/antagonistas & inibidores , Progesterona/farmacologia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Coelhos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/metabolismo , Ativação TranscricionalRESUMO
An efficient approach to 17-chloro-16(17) unsaturated D-homo antiprogestins is described. The key steps of the synthesis are a ring-expansion via dichlorocarbene addition to a 17-silyl enol ether and a palladium catalyzed coupling of an 11 beta-(4-aryltriflate) with tributyl(1-ethoxyethenyl)stannane or diethyl(3-pyridinyl)-borane. The new progesterone antagonists were tested for their biological activities and compared to those of known antiprogestins.
