LXR subtype selective agonists

The apparent liabilities of LXRa p dual agonists coupled with data garnered from LXR KO studies have led to a strong emphasis on the identification of LXR subtype selective agonists suitable for pharmacologic evaluation. Two natural products (57, 58) have been newly identified as LXRa-selective agonists with efficacy in cell-based assays (IC50 a p 0.12 > 15 and 1.3 50 mM, respectively) 147 . Riccardin C (59) was identified as a LXRa agonist and a LXRp antagonist 148 unfortunately it exhibits...

PPARac dual agonists

As clinical evidence suggests both hyperglycemia and dyslipidemia (e.g. atherosclerosis) contribute to morbidity, single entity PPARa g dual agonists may confer broad benefits in the diabetic population. Indeed, concomitant therapy using rosi-glitazone and fenofibrate yielded complementary effects on glycemic and lipid parameters with few adverse events 53 . While preclinical evaluation of PPARa g dual agonists is confounded by PPARa-mediated reductions of hyperglycemia or hyperinsulinemia in...

Conclusion

Clearly there is a large amount of research being done in the search for new antidepressants. Due to space limitations, this review has highlighted only some of the strategies being pursued. Other emerging areas of research include the modulation of glutamatergic neurotransmission 53 , GABA 54 , cytokines 55,56 , and neurotrophins 57 . While much research remains focused on direct modulation of monoaminergic systems, other strategies involve manipulation of separate biological systems that are...

Peroxisome proliferatoractivator receptor gamma PPARg

Peroxisome proliferator-activated receptors (PPARs) are orphan receptors belonging to the steroids thyroid retinoid receptor super family of ligand-activated transcription factors. There are three PPAR isoforms (PPARa, -p, -g), each of which is differentially expressed and displays a distinct pattern of ligand specificity 50 . PPARs are implicated in several physiological processes, such as the regulation of lipoprotein, lipid metabolism and glucose homeostasis. Recent observations indicate...

The mechanism of GK activation by allostericsite binders

In a search for molecules that disrupt the GK-GKRP complex, compounds that directly activate GK by binding to an allosteric site of the enzyme were se-rendipitously discovered. The GKAs were shown to increase the affinity of GK for glucose (lower S0.5), and to increase the Vmax, although not all GKAs share the latter characteristic. The degree of positive cooperativity with respect to glucose decreased in the presence of a GKA, as reflected by a decrease in Hill slope from around 1.5-1.7 to...

Melanocortin MC4 antagonists

Melanocortins participate in the HPA axis response to stress, at least partly through the release of CRF. The MC4 receptor has been identified as the receptor of particular interest in relationship to stress-related disorders including anxiety and depression 45 . The non-peptide MC4 antagonist MCL0129, 24, (K 7.9 nM) demonstrated antidepressant effects in the forced swim and learned helplessness models, and also showed anxiolytic activity after oral administration 46 . Interestingly, the same...

Serotonin 5HT2C receptor agonists

The serotonin (5-HT) receptor family are among the most studied of the neurotransmitters. The 5-HT2C receptor subclass has seen a great deal of research during the past 10 years, and evidence has established the potential as a target for treating anxiety, depression 107 , schizophrenia 108,109 and most notably obesity 110,111 . Until recently, attaining selectivity in the 5-HT2C receptor subclass over the closely related 5-HT2A and 5-HT2B receptors had been elusive, but selective agents are now...

Neuroprotection by polyADPribosepolymerase inhibitors

Poly(ADP-ribose) polymerase-1 (PARP-1) is a chromatin-bound nuclear enzyme involved in a variety of physiological functions related to genomic repair, including DNA replication and repair, cellular proliferation and differentiation, and apoptosis 30 . PARP-1 functions as a DNA damage sensor and signaling molecule. Upon binding to DNA breaks, activated PARP cleaves NAD + , the nicotin-amide, and ADP-ribose and polymerizes the latter into nuclear acceptor proteins including histones,...

Corticotropinreleasing factor

Corticotropin-releasing factor (CRF) is a well-known regulator of the hypothalamic-pituitary-adrenal (HPA) axis, which is activated in response to stress. Hyperactivity of the HPA axis has been linked to depression in humans, and both the elevation of CRF concentrations in the cerebral spinal fluid (CSF) and an increase in the number of CRF-containing neurons in the paraventricular nucleus have been observed in depressed patients. In addition, some antidepressants (e.g., desipramine and...

Neuroprotection by caspase inhibitors

Caspases are a family of cysteine proteases that are expressed as inactive zymogens and undergo proteolytic maturation in a sequential manner in which initiator caspases cleave and activate the effector caspases 3, 6 and 7. Caspase-3, among effector caspases, has been implicated in neuronal apoptosis during normal brain development and in delayed neuronal cell death after brain injury 17,18 . The latter observations have suggested that this is a potential therapeutic target which has led to the...

Carbon and nitrogencentered glucokinase activators

Investigation of small-molecule GKAs has rapidly turned into an extremely dynamic area of diabetes research and was recently reviewed 2 . Since the emergence of initial reports 7 , numerous pharmaceutical companies have initiated drug discovery projects to identify small-molecule GKAs. To seek out small molecules that increase GK enzymatic activity, a library of 120,000 structurally diverse synthetic compounds was screened. A solitary hit was identified from this high-throughput screening (HTS)...

Covalent binding

Availability of a radiolabeled compound allows a quantitative assessment of the amount of covalent binding either in vitro or in tissue or blood plasma obtained from preclinical in vivo studies. To assess the impact of metabolic bioactivation, the compound is usually incubated with human liver microsomes. Following incubation, the solution is centrifuged and the supernatant is removed. The macromolecular pellet (in particular proteins) has to be washed extensively (i.e., multiple...

Indole acetic acid derivatives

4-Indole acetic acid derivatives as DP antagonists, exemplified by 8a, 8b and 8c, were derived from 3-indole acetic acids 35 . Compounds 8a, 8b and 8c demonstrated binding K values of 10, 13 and 33 nM, respectively, in 3H -PGD2 binding assays using mDP expressing CHO cell membranes. They also inhibited PGD2-induced cAMP formation in mDP expressing CHO cells in the presence of 0.1 BSA at IC50 values of 0.3, 0.43 and 0.57 mM, respectively 36 . Greater than 200fold selectivity was achieved with 8a...

Indole acetic acid derivatives and related compounds

Compound Acid

Numerous 1-indole acetic acid derivatives compounds have been reported as CRTH2 antagonists. These include the tetrahydrocarbazole derivative 17, Rama-troban (BAY U3405), which is currently marketed in Japan for allergic rhinitis 51 . Ramatroban was developed as a thromboxane A2 receptor (TP) antagonist later it was also shown to be a CRTH2 antagonist. Ramatroban has been reported to reduce antigen-induced early and late-phase allergic responses in mice, rats and guinea pigs. In humans,...

Prokinetic Agent Target Classes 21 Dopamine D2 receptor antagonists

Blockade of D2 receptors present on enteric neurons and or those located at the chemoreceptor trigger zone may promote motility. In fact, D2 receptor antagonists such as metoclopramide and domperidone are in use for the treatment of dyspeptic symptoms, despite potential side effects such as hyperprolactinemia and extrapyramidal dystonic reactions 1 . Itopride 1, which is available on the market in Japan, is a D2 receptor antagonist, which also exhibits acetylcholine esterase inhibition. The...

Introduction

The worldwide frequency of idiopathic obesity has increased significantly over the last decade 1 , and the estimated annual direct and indirect cost in the US alone due to obesity is 117 billion 2 . Individuals classified as obese (body mass index (BMI)> 30) have a significantly higher risk of mortality and related comorbidities, such as insulin resistance and type 2 diabetes, dyslipidemia, and hypertension 1,3 . The clustering of obesity (abdominal obesity in particular) with insulin...

Early DP antagonists and their related analogs

BW A868C (2) is one of the early DP antagonists reported in the literature. It binds the DP receptor with a Kd value of 1.45 nM (Kd was determined using human platelets) 28 . S-5751 (3) was the first DP antagonist reported to be under evaluation in clinical trials for rhinitis and asthma 29 . S-5751 demonstrated binding IC50 value of 1.9 nM in 3H -PGD2 binding assays using human platelet membranes. It also inhibited PGD2-induced cAMP formation in human platelets with an IC50 of 0.9 nM 30 ....

Small molecule agonists

Although the peptide oxytocin analogue carbetocin (17, Duratocin, Kd 1.96 nM at OT receptor) is used in the clinic, it has affinity for the myometrial human vasopressin V1 receptor (Kd 7.24 nM), and the renal vasopressin V2 receptor (Kd 61.3 nM) 36 . In addition, carbetocin (17) has antagonistic properties against oxytocin in vitro (pA2 8.21) and hence is considered a partial agonist antagonist at the OT receptor 37 . Carbetocin (17) is given by intramuscular injection in contrast to oxytocin,...

HT6R antagonists

The 5-HT6 receptor (5HT6R) is expressed almost exclusively in the CNS. Several pharmacological studies and genetic models support a role for this receptor in obesity. 5HT6R KO mice were found to be resistant to body weight gain on a high fat diet 101 . Administration of 5HT6R antisense oligonucleotide complementary to bases 1-18 of the rat 5HT6R cDNA initiation sequence was shown to reduce both food intake and body weight of diet-induced obese rats over a 6-day period 102 . A brain penetrant...

Cb1r Antagonists

The endocannabinoid system consists of endogenous ligands (i.e., anandamide and 2-arachidonoyl glycerol) that bind to and activate either of two receptor subtypes, CB1R or CB2R, that are distributed throughout the periphery (gut, liver, spleen, immune cells) and the CNS 4,5 . Endocannabinoids and exogenous can-nabinoids (notably A9-tetrahydrocannabinol, the principal active constituent in Cannabis sativa L., or marijuana) have been shown to stimulate appetite 6 . CB1R was hypothesized to play a...

Antioxidants

It was established in 1993 that activation of VCAM-1 expression on endothelial cells is partly regulated by a redox signal transduction pathway that is sensitive to inhibition by antioxidants. Pyrrolidine dithiocarbamate (PDTC), a known antioxidant, at 50 mM inhibited over 90 of IL-1p-induced VCAM-1 expression in cultured human umbilical vein endothelial cells (HUVEC) 47,48 . These findings led to the search for new compounds with antioxidant properties as inhibitors of VCAM-1 expression....

Doripenem Antibiotic [2225

Country of origin Originator First introduction Introduced by Trade name CAS registry no Molecular weight Doripenem is a parenteral carbapenem antibiotic launched last year in Japan for the treatment of bacterial respiratory and urinary tract infections. It is a 1p-methyl carbapenem derivative, and it is the fourth analog to be marketed in this series following the launch of meropenem, biapenem, and ertapenem in previous years. The introduction of a 1 p-methyl group to the carbapenem skeleton...

Gene Expression Profiling

Genom-wide RNA expression analysis has become a standard tool in the arsenal of the pharmaceutical researcher. Until recently, analysis of expression data consisted of the extraction of lists of genes that were statistically significantly up- or 5.40 4.35 3.30 2.25 2.20 2.15 1.90 1.65 1.50 1.35 Genes with a fold change of 2.0 and above the usual cutoff selected for analysis of statistical significance and further study differential values - fc- Sort data by 5.40 4.35 3.30 2.25 2.20 2.15 1.90...

Ciclesonide Asthma Copd [69

Trade name CAS registry no Molecular weight Altana Aventis Teijin Alvesco 126544-47-6 540.69 Ciclesonide, a new inhaled corticosteroid (ICS), is indicated for the prophylactic treatment of persistent asthma. ICS treatment is a widely accepted standard of care for maintenance therapy of chronic asthma, and the currently available agents include fluticasone propionate, budesonide, triamcinolone acetonide, flunisolide, and beclomethasone dipropionate. These agents exert their potent...

Emerging Mechanisms And Conclusions

Schizophrenia is the focus of intense preclinical and clinical research and is an area in which discoveries in the basic sciences are rapidly reviewed in the context of their potential therapeutic implications. Although it is not feasible to cover either the depth or breadth of the available subject matter in a review of this size, we will conclude with a brief mention of potential targets awaiting the development of the necessary biology and chemistry to establish their importance in this...

Therapeutic Potential

First cloned in 1989 10 , VCAM-1 is an inducible cell surface protein of vascular endothelial cells. It is normally absent on resting cells, but is readily induced by a wide variety of inflammatory factors, such as interleukin-1 (IL-1), bacterial lipo-polysaccharide (LPS), and tumor necrosis factor-a (TNF-a) 11,12 . At sites of inflammation, VCAM-1 can be cleaved from cell surface as soluble VCAM-1 (sVCAM-1) that can be detected in serum and other body fluids. VCAM-1 has been implicated in the...

Darifenacin Urinary Incontinence [1518

Darifenacin demonstrates greater effect on tissues in which the predominant receptor type is M3 rather than Ml or M2. In vitro darifenacin inhibits carbachol-induced contractions with greater potency in isolated guinea-pig bladder (M3) than in guinea-pig atria (M2) or dog saphenous vein (Ml). In animal models, it shows greater selectivity for inhibition of detrusor contraction over salivation or tachycardia. The synthesis of darifenacin involves the coupling of 5-(2-bromoethyl)-2,...

Rasagiline Parkinsons Disease [7987

Country of origin Originator First introduction Introduced by Trade name CAS registry no (mesylate salt) 171.24 267.33 (mesylate salt) Rasagiline is a second-generation, irreversible monoamine oxidase type B (MAO-B) inhibitor that has been launched for the treatment of Parkinson's disease (PD). Unlike its predecessor selegiline, it is not metabolized to amphetamine derivatives and is, therefore, devoid of the sympathomimetic activity responsible for adverse side effects. Rasagiline is, however,...

Potential Therapeutic Indications

Several lines of evidence implicate elevated 11p-HSD1 activity in the etiology and or maintenance of type 2 diabetes and metabolic syndrome. There is a higher level of 11p-HSD1 mRNA and activity in adipose tissue of obese humans 11,12,14,39 and rodents 40 . Chronic high-fat feeding decreases 11 p-HSD1 activity and mRNA in fat of C57Bl 6J mice, suggesting that this serves as an adaptive mechanism attempting to protect against the adverse metabolic consequence of high-fat feeding 41 ....

Ispinesib and related compounds

Clinical progress on ispinesib and SB-743921 Ispinesib (SB-715992 CK0238273, 2), one member of a KSP inhibitor series bearing a quinazolinone core, was the first mitotic kinesin inhibitor to enter clinical trials. Like its earlier reported analog 1, ispinesib was reported to be an allosteric inhibitor of KSP that binds at the motor domain and inhibits its ATPase activity in an ATP uncompetitive manner. It was also shown to be > 70,000-fold selective for KSP versus other members of the...

Lumiracoxib Antiinflammatory [4851

As a second-generation, selective cyclooxygenase (COX-2) inhibitor, lumiracoxib is devoid of the gastrointestinal issues that plague other non-selective, non-steroidal, anti-inflammatory drugs (NSAIDs) that crossover to COX-1. As an inhibitor of the inducible COX-2 that is up-regulated in pathological processes of pain and inflammation, lumiracoxib blocks the conversion of arachidonic acid to prostaglandins, the mediators of the pathological effects. It's mode of binding to COX-2 has been found...

Tigecycline Antibiotic [97103

The emergence of drug-resistant bacteria has diminished the clinical utility of the tetracyclines. Research to circumvent the efflux and ribosomal protection mechanisms of bacteria has led to the development of the glycylcyclines. Tigecycline is the first glycylcycline antibiotic to launch for the parenteral treatment of baterial infection, including complicated intra-abdominal and skin infections. Its mechanism of action involves inhibiting protein translation in bacteria by binding to the 30S...

Deferasirox Chronic Iron Overload [1921

Iron overload is a potentially life-threatening cumulative toxicity that occurs frequently in patients who receive multiple blood transfusions for the treatment of certain types of chronic anemias such as thalassemia and sickle-cell disease, as well as for the treatment of myelodysplastic syndromes. Progressive iron overload, if untreated, often causes injury to heart, liver, endocrine organs, joints, and other target cells and tissues. Iron overload is treated by administration of iron...

Nepafenac Antiinflammatory [5255

Nepafenac, launched last year by Alcon Laboratories, is a topical ophthalmic medication indicated for the treatment of ocular pain and inflammation associated with cataract surgery. Nepafenac is a prodrug of amfenac, which is an NSAID and a potent non-selective inhibitor of COX-1 IC50 0.25 mM and COX-2 IC50 0.15 mM . Nepefenac itself exhibits only weak activity against COX-1 IC50 64.3 mM . Amfenac Fenazox has been marketed in Japan since 1986 for the treatment of rheumatoid arthritis,...

Ramelteon Insomnia [7378

Unlike most treatments of insomnia that target the GABA g-aminobutyric acid receptor complex, ramelteon is an agonist of the melatonin receptor. In particular, it has high selectivity for the MT1 and MT2 subtypes, which have been implicated in the maintenance of circadian rhythms, over the MT3 receptor responsible for other melatonin functions. Its lack of affinity for not only the GABA receptor complex but also neurotransmitter, dopaminerigic, opiate, and benzodiazepine receptors suggests an...

Udenafil Erectile Dysfunction [111115

Animal Human Coupling

Introduction Introduced by Trade name CAS registry no Molecular Weight Udenafil is the fourth in a class of drugs targeting the inhibition of the enzyme phosphodiesterase 5 PDE5 for the treatment of erectile dysfunction. Inhibition of PDE5 results in the increase in endogenous cyclic guanosine monophosphate cGMP concentrations in the penile corpus cavernosum. cGMP induces smooth muscle cell relaxation and subsequent increased blood flow leading to a sustainable erection. Udenafil is a potent...

Luliconazole Antifungal [4547

Country of origin Originator First introduction Introduced by Trade name CAS registry no Molecular weight Nihon Nohyaku Pola Lulicon 187164-19-8 354.28 Luliconazole is a member of the imidazole class of antifungal agents, with specific utility as a dermatological antimycotic drug. It was launched last year in Japan as a topical agent for the treatment of athlete's foot. Luliconazole is an optically active drug with R -configuration at its chiral center. It is structurally related to...

Prodrugs Of Poorly Soluble Compounds

Compounds are considered to be poorly soluble when their oral bioavailability is limited by the rate and extent of dissolution in the gastrointestinal GI tract. ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOLUME 41 ISSN 0065-7743 DOI 10.1016 S0065-7743 06 41027-7 2006 Elsevier Inc. All rights reserved A typical prodrug strategy in such cases focuses on chemical derivatization to improve water solubility. Highly polar, ionizable pro-moieties are often required to obtain an adequate level of...

GHSR antagonists

Ghrelin is an octanoylated 28 amino acid peptide hormone that is synthesized principally in the oxyntic mucosal cells of the stomach. It binds to and activates the growth hormone secretagogue receptor GHSR ghrelin receptor which is expressed primarily but certainly not exclusively in the hypothalamus and the pituitary gland 54 . Intravenous administration of ghrelin has been reported to increase food intake in rodents and humans 55,56 . Plasma ghrelin levels rise pre-prandially and fall...