Mini-Reviews in Medicinal Chemistry, Volume 5, No. 8, 2005
Contents
Nuclear
Receptors as Drug Discovery Targets
Executive
Editor: Sunil Nagpal
Editorial Pp.699-700
Sunil
Nagpal
Non-Steroidal Progesterone Receptor Specific
Ligands Pp.701-708
G.F.
Allan and Z. Sui
Molecular Mechanisms of Mineralocorticoid
Receptor Antagonism by Eplerenone Pp.709-718
Xiao
Hu, Suzhen Li, Ellen G. McMahon, Deepak S. Lala and Amy E. Rudolph
FXR, A Therapeutic Target for Bile Acid and
Lipid Disorders Pp.719-727
Stefan
Westin, Richard A. Heyman and Richard Martin
The Pharmacology of LXR Pp.729-740
Laura
F. Michael, Jeffrey M. Schkeryantz and Thomas P. Burris
PPARs as Targets for Metabolic and
Cardiovascular Diseases
Pp.741-753
Peter
T.W. Cheng and Ranjan Mukherjee
Retinoids as Therapeutic Agents: Today and
Tomorrow Pp.755-760
Valerie Vivat-Hannah and F. Christopher Zusi
Vitamin D Receptor Modulators for
Inflammation and Cancer
Pp.761-778
Ying K. Yee, Subba R. Chintalacharuvu, Jianfen Lu and Sunil Nagpal
Abstracts
[Back to top] Editorial
Sunil
Nagpal
Nuclear receptor
(NR) proteins are ligand-dependent transcription factors that belong to the
superfamily of steroid/thyroid/retinoid/vitamin D receptors. NR family members
play important roles in cell growth, differentiation, homeostasis, metabolism
and development. NRs are modular proteins that contain three distinct
functional domains. An N-terminal domain containing a ligand-independent
activation function, AF-1, a middle zinc-finger containing DNA binding domain (DBD)
and C-terminal ligand binding domain (LBD) that also harbors a ligand-dependent
transactivation function, AF-2. The activity of NR proteins is modulated by
ligand binding to their LBDs that results in a conformational change leading to
either transactivation or transrepression of target gene expression in a
cell/tissue and promoter/gene-context dependent manner. NRs are one of the best
therapeutic targets since their activities could be modulated by small
molecules, leading to subtle changes in gene expression in the desired
direction and normalization of the altered physiological/pathological
phenotype.
In the past
decade, a number of molecular, genetic, structural and pharmacological studies
have contributed to increased understanding of the molecular pathways involved
in NR action. These studies have identified not only novel mechanisms of NR
action but also provided new disease targets for small molecule ligands. These
studies in addition have yielded novel molecular assays for the rapid
identification of compounds with the desired pharmacological profile and have
helped set a stage for the rational design of the next generation of
pharmaceuticals. There are 48 members of the NR superfamily in the human
genome. Interestingly, all the NRs (except LXR), whose ligands are known, are
successful therapeutic targets. Therefore, synthetic and/or natural ligands of
steroid hormone receptors (AR, MR, PR and GR), RAR, RXR, VDR, TR and PPAR, are
currently marketed drugs (Table I).
Further, the
involvement of even orphan NRs whose ligands have not been identified, and
LXRs, in important physiological or metabolic processes provides the rest of
NRs with a high level of validation as potential therapeutic targets. NR based
drugs account for approximately 10-15% of the total worldwide pharmaceutical
market. Most of these drugs are best currently available options for the
treatment of conditions associated with significant morbidity and mortality. A
number of these treatments are currently in vogue even though their use is
accompanied by unwanted side effects. For example, although glucocorticoids (GR
agonists), one of the most successful classes of pharmaceuticals, are widely
used for the treatment of inflammatory diseases (rheumatoid arthritis, systemic
lupus erythematosus, ulcerative colitis, Crohn’s disease, etc.), their use is
associated with osteoporosis, hyperglycemia, hypertension, sleep disturbances
and psychosis. Similarly, topical corticosteroids cause skin thinning and
tachyphylaxis and thus cannot be applied for generally more than two weeks.
Therefore, there is an urgent need for the development of safer oral and
topical glucocorticoids without the above-mentioned side effects. PPARg ligands, Actos and Avandia, are medicines of
choice for the treatment of type II diabetes but their use is accompanied by
unwanted side effects of weight gain and edema. Further, widespread use and
development of VDR ligands for osteoporosis and inflammatory indications is
hampered by their undesired side effect of hypercalcemia/hypercalciuria.
Increased biology of NR action has resulted in the elucidation of the
mechanisms underlying therapeutic actions and side effects. Recently,
considerable pharmaceutical research has been directed towards identifying
efficacious NR ligands devoid of their classical side effects. While it is not
possible to cover all the NRs in a single issue, here a number of leading drug
hunters provide a glimpse in the drug discovery efforts on selected members of
this superfamily (MR, PR, Retinoid Receptors, FXR, VDR, PPARs and LXRs). In
this decade, we hope to see the emergence of novel drugs from some of these
efforts.
[Back to top] Non-Steroidal Progesterone Receptor Specific
Ligands
G.F.
Allan and Z. Sui
The nuclear receptor
for progesterone is a target for contraception and for several therapeutic
indications. Progestin agonists and antagonists in clinical use mimic the
steroidal backbone of the cognate ligand, progesterone. Thus, they have
significant cross-reactivity with other steroid receptors. Recently,
non-steroidal progesterone receptor ligands have begun to appear in the
literature. This review will describe the current status of research into these
promising new chemical entities.
[Back to top] Molecular Mechanisms of Mineralocorticoid
Receptor Antagonism by Eplerenone
Xiao
Hu, Suzhen Li, Ellen G. McMahon, Deepak S. Lala and Amy E. Rudolph
Mineralocorticoid
receptor (MR) antagonism has proven to effectively attenuate the pathophysiological
effects of aldosterone in clinical and experimental settings of hypertension
and heart failure. MR activates transcription of target genes upon aldosterone
binding, and eplerenone selectively binds to MR and blocks aldosterone-
mediated activation. In this review, we summarize the preclinical and clinical
evidence supporting the beneficial effects of eplerenone (INSPRATM),
a selective aldosterone blocker, in the treatment of hypertension and heart
failure. We also review the current status in understanding the molecular
mechanisms of action of the MR and its ligand. In addition, we compare the
effects of eplerenone and spironolactone, a nonselective aldosterone blocker,
on the transcriptional activity of MR and provide a molecular explanation for the
improved side-effect profile of eplerenone compared with spironolactone.
[Back to top] FXR, A Therapeutic Target for Bile Acid and
Lipid Disorders
Stefan
Westin, Richard A. Heyman and Richard Martin
The farnesoid X
receptor (FXR) is a nuclear receptor expressed in tissues exposed to high
concentrations of bile acids such as the liver, kidney and intestine and
functions as a bile acid sensor. FXR regulates the expression of various
transport proteins and biosynthetic enzymes crucial to the physiological
maintenance of lipids, cholesterol and bile acid homeostasis. The concept of
reverse endocrinology, whereby the receptor is identified first, followed by
the identification of ligands and the sequential elucidation of the physiological
role of the receptor has been widely used for a number of orphan nuclear
receptors. The design of synthetic high affinity ligands acting via
these receptors not only helps to decipher the function of the receptor, but
also should lead to the development of novel and highly specific drugs. The
bile acid receptor FXR is a perfect example where this strategy helped with
understanding the role of this receptor in cholesterol and bile acid
homeostasis. Regulation of FXR through small-molecule drugs represents a
promising therapy for diseases resulting from lipid, cholesterol and bile acid
abnormalities.
[Back to top] The Pharmacology of LXR
Laura
F. Michael, Jeffrey M. Schkeryantz and Thomas P. Burris
Liver X receptors
(LXRs) are members of the nuclear hormone receptor superfamily of
ligand-activated transcription factors. Two LXRs (LXRa and LXRb)
were initially characterized as orphan members of this superfamily with
disparate patterns of tissue expression. These two receptors later were
recognized as sterol-responsive with the ability to directly bind several
oxysterol metabolites. Many LXR target genes have been identified that
implicate these receptors in a variety of physiological processes including
cholesterol transport and metabolism, glucose metabolism, and inflammation.
Synthetic LXR ligands have been designed with the potential to treat disorders
such as atherosclerosis and diabetes. In this review, we describe the potential
utility of LXR ligands in the treatment of disease.
[Back to top] PPARs as Targets for Metabolic and
Cardiovascular Diseases
Peter
T.W. Cheng and Ranjan Mukherjee
Peroxisome
proliferator-activated receptors (PPARs) alpha, gamma and delta (beta) are
ligand-activated transcription factors of the nuclear hormone receptor
superfamily which have been shown to play key roles in maintaining glucose and
lipid homeostasis. The physiological effects of several marketed drugs for the
treatment of dyslipidemia (fenofibrate and gemfibrozil) and diabetes
(rosiglitazone and pioglitazone) have now been shown to be mediated through
PPARalpha and PPARgamma respectively. Over the past few years our understanding
of how PPAR ligands and receptors modulate gene expression has greatly
increased; this knowledge is being used to design even more potent and
efficacious PPAR ligands for the treatment of diabetes, dyslipidemia,
atherosclerosis and obesity. This review is a brief survey of the PPAR field
which highlights recent progress, with an emphasis on new ligands with novel
PPAR profiles, particularly compounds which are co-agonists of PPAa, g and
b (d).
[Back to top] Retinoids as Therapeutic Agents: Today and Tomorrow
Valerie Vivat-Hannah and F. Christopher Zusi
Retinoids have
shown beneficial therapeutic effects in pre-clinical and animal models for
multiple pathologic indications, however severe adverse effects, restricting
dosage and efficacy of oral formulations limit their use in patients. The focus
of this review includes the actual medicinal use of retinoids and chemical
efforts to generate highly selective and less toxic synthetic retinoids.
[Back to top] Vitamin D Receptor Modulators for Inflammation and Cancer
Ying K. Yee, Subba R. Chintalacharuvu, Jianfen Lu and
Sunil Nagpal
1a, 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 immunomodu-latory
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.