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.
ABSTRACT
SAR about the B-ring of a series of N(2)-aroyl anthranilamide factor Xa (fXa) inhibitors is described. B-ring o-aminoalkylether and B-ring p-amine probes of the S1' and S4 sites, respectively, afforded picomolar fXa inhibitors that performed well in in vitro anticoagulation assays.
Subject(s)
Antithrombin III/chemical synthesis , Factor Xa Inhibitors , Fluorescent Dyes/pharmacology , ortho-Aminobenzoates/pharmacology , Anticoagulants/chemistry , Antithrombin III/chemistry , Binding Sites , Chemistry, Pharmaceutical/methods , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Fluorescent Dyes/chemical synthesis , Humans , Kinetics , Models, Chemical , Molecular Conformation , Structure-Activity Relationship , ortho-Aminobenzoates/chemical synthesisABSTRACT
Vitamin D receptor (VDR) ligands are therapeutic agents for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. VDR ligands also show immense potential as therapeutic agents for autoimmune diseases and cancers of skin, prostate, colon, and breast as well as leukemia. However, the major side effect of VDR ligands that limits their expanded use and clinical development is hypercalcemia that develops as a result of the action of these compounds mainly on intestine. In order to discover VDR ligands with less hypercalcemia liability, we sought to identify tissue-selective VDR modulators (VDRMs) that act as agonists in some cell types and lack activity in others. Here, we describe LY2108491 and LY2109866 as nonsecosteroidal VDRMs that function as potent agonists in keratinocytes, osteoblasts, and peripheral blood mononuclear cells but show poor activity in intestinal cells. Finally, these nonsecosteroidal VDRMs were less calcemic in vivo, and LY2108491 exhibited more than 270-fold improved therapeutic index over the naturally occurring VDR ligand 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in an in vivo preclinical surrogate model of psoriasis.
Subject(s)
Acetates/pharmacology , Arylsulfonates/pharmacology , Receptors, Calcitriol/metabolism , Thiophenes/pharmacology , Vitamin D/analogs & derivatives , Vitamin D/pharmacology , Acetates/chemical synthesis , Acetates/metabolism , Animals , Arylsulfonates/chemical synthesis , Arylsulfonates/metabolism , Caco-2 Cells , Calcitriol/metabolism , Calcitriol/pharmacology , Cell Proliferation , Cells, Cultured , Colonic Neoplasms/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Female , Humans , Hypercalcemia/metabolism , Intestines , Keratinocytes/drug effects , Keratinocytes/metabolism , Ligands , Mice , Mice, Hairless , Mice, Inbred C57BL , Mice, Inbred Strains , Models, Biological , Osteoblasts/drug effects , Osteoblasts/metabolism , Psoriasis/drug therapy , Rats , Receptors, Calcitriol/agonists , Signal Transduction , Species Specificity , Thiophenes/chemical synthesis , Thiophenes/metabolism , Transcription, Genetic , Tumor Cells, Cultured , Vitamin D/chemical synthesis , Vitamin D/metabolismABSTRACT
1alpha, 25-Dihydroxyvitamin D3 [1,25-(OH)2D3], the biologically active form of vitamin D, is an important hormone that is critically required for the maintenance of mineral homeostasis and structural integrity of bones. 1,25-(OH)2D3 accomplishes this by facilitating calcium absorption from the gut and by a direct action on osteoblasts, the bone forming cells. Apart form its classical actions on the gut and bone, 1,25-(OH)2D3 and its synthetic analogs also possess potent anti-proliferative, differentiative and immunomodulatory activities. 1,25-(OH)2D3 exerts these effects through vitamin D receptor (VDR), a ligand-dependent transcription factor that belongs to the superfamily of steroid/thyroid hormone/retinoid nuclear receptors. The presence of VDR in various tissues other than gut and bone, along with their ability to exert differentiation, growth inhibitory and anti-inflammatory action, has set the stage for therapeutic exploitation of VDR ligands for the treatment of various inflammatory indications and cancer. However, the use of VDR ligands in clinic is limited by their major dose-related side effect, namely hypercalcemia/hypercalciuria. Efforts are being undertaken to develop vitamin D receptor modulators (VDRMs) that are tissue-selective and/or gene-selective in their action and these ligands may exhibit increased therapeutic indices. This review explores the recent advances in VDR biology, non-secosteroidal VDR ligands and the current and potential clinical applications of VDR ligands in inflammation and cancer.
Subject(s)
Antimetabolites/therapeutic use , Bone Diseases, Metabolic/drug therapy , Calcitriol/pharmacology , Inflammation/drug therapy , Neoplasms/drug therapy , Receptors, Calcitriol/metabolism , Transcription Factors/metabolism , Animals , Calcitriol/chemistry , Calcium/metabolism , Calcium Metabolism Disorders/chemically induced , Calcium Metabolism Disorders/prevention & control , Chemistry, Pharmaceutical , Homeostasis/physiology , Humans , Ligands , Osteoblasts/metabolism , Receptors, Calcitriol/agonists , Receptors, Calcitriol/antagonists & inhibitors , Transcription Factors/geneticsABSTRACT
1alpha, 25-dihydroxyvitamin D3 [1,25 (OH)(2)D(3)], the active metabolite of vitamin D3, is known for the maintenance of normal skeleton architecture and mineral homeostasis. Apart form these traditional calcemic actions, 1,25 (OH)(3)D(1) and its synthetic analogs are increasingly recognized for their potent anti-proliferative, prodifferentiative and immunomodulatory activities. The calcemic and non-calcemic actions of 1,25 (OH)(2)D(3) and its synthetic analogs are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25 (OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential applications of VDR ligands in inflammation, dermatological indications, osteoporosis, cancers and autoimmune diseases. VDR ligands have shown therapeutic potential in limited clinical trials as well as in animal models of these diseases. As a result, a VDR ligand, calcipotriol is in clinic for psoriasis and another, OCT, [2-oxa-1,25 (OH)(2)D(3)] is being developed as a topical agent for the same indication. Further, 1alpha,-hydroxyvitamin D3 (alphacalcidol), a prodrug of 1,25 (OH)(2)D(3) is in clinic and a synthetic VDR ligand, ED-71, is under consideration for approval in Japan for the treatment of osteoporosis. Interestingly, VDR ligands have shown not only preventive but also potent therapeutic anabolic activities in animal models of osteoporosis. However, the wide spread use of VDR ligands in above-mentioned indications is hampered by their major side effect, namely hypercalcemia. In view of this associated toxicity, synthetic VDR ligands with reduced calcemic potential have been synthesized with the ultimate aim of improving their therapeutic efficacy. This review presents recent advances in VDR biology, novel VDR ligands and therapeutic applications of VDR ligands.
