Preclinical data

The discovery of Maraviroc (MVC, UK-427,857) has been recently described 20-24 . Accordingly, ligand 1 emerged from the high throughput screen of the compound collection in CCR5- expressing HEK-293 against MIP-1p (Figure 1). Subsequent chemistry optimization and removal of the pyridyl imidazole nitrogen, thought to be involved in a potent inhibition of 2D6 P450 cytochrome by 1, yielded analogue 2. The high lipophilicity of 2 was then in turn addressed by introducing the more polar amide moiety...

Competitive inhibitors

Competitive inhibitors of GST P1-1 fall under two categories non-glutathione-and glutathione-based compounds. The former group covers a broad range of chemical structures such as tricyclic-based dibenzazepines, polyphenolic natural products, alkaloids, pyrimethamine, and dyes. The latter group, as its name indicates, covers compounds whose main structure or backbone is that of GSH. 2.2.1 Non-glutathione-based small molecules Tricyclic antidepressants such as imipramine (25), clomipramine (26),...

Serms For Hot Flushes

Hot flushes (flashes) are characterized by a warming sensation that begins in the chest and moves towards the neck and head, and are often accompanied by sweating, palpitations and cutaneous flushing. The episodes generally last from 30 s to 10min. The majority of postmenopausal women experience hot flushes, with a significant percentage of these women continuing to suffer symptoms for more than 5 years 13,14 . The hot flush event is thought to be centrally mediated, resulting from a transient...

Other Novel Serm Scaffolds

Despite the discovery of ERa selective SERMs and their subsequent use as chemical tools to evaluate the pharmacological significance of this receptor subtype, the respective roles that ERa and ERp play in regulating tissue selectivity is not yet clear. As a result, the identification of non-receptor subtype selective SERMs remains of considerable interest. Along these lines, isochroman 26 and isothiochroman 27 have been prepared based on structural analogy to lasofoxifene 52 . Compound 27...

New Biology

The standard model for the preclinical development of anti-osteoporosis therapies is the ovariectomized (OVX) rat. However, Cat K inhibitors developed specifically against the human enzyme are generally significantly less potent ( 2-orders of magnitude) against the rat and mouse enzymes than against human Cat K 9 . This loss of potency towards the rodent enzymes, which is consistent with their low sequence homology, therefore restricts the use of pharmacological inhibitors in rodent...

Analgesia

Conflicting evidence exists with both agonists and antagonists in pain models that confound the potential role of H3 antagonists in analgesia 12,32 . The H3 agonist immepip administered systemically or intrathecally had analgesic effects in models for mechanical but not thermal pain, the latter a profile absent in H3R knockout mice 33 . In contrast, the non-selective antagonist, thioperamide had antinociceptive effects in hotplate and writhing tests 34 . A large number of H3 antagonists have...

Panitumumab

Country of origin Originator First introduction Introduced by Trade name CAS registry no Molecular weight Expression system Manufacturer Panitumumab is a recombinant, fully human IgG2 kappa monoclonal antibody that is highly selective for the epidermal growth factor receptor (EGFR), and it is indicated for the treatment of EGFR-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy...

Lubiprostone

Country of origin Originator First introduction Introduced by Trade name CAS registry no Molecular weight (Chronic idiopathic constipation) US Sucampo Takeda Amitiza 333963-40-9 390.46 (Chronic idiopathic constipation) US Sucampo Takeda Amitiza 333963-40-9 390.46 Chronic constipation is an affliction affecting 4-5 million Americans alone. When no specific cause is identified, it is classified as idiopathic. Dietary and lifestyle modifications are the first-line conventional approaches followed...

New MLT agonist structures

Tricyclic compounds, namely those bearing the scaffold dibenzo a,d cycloheptene, have been described as melatonin receptor ligands with MT2 receptor selectivity. Noticeably, 14 is described as an MT2 selective receptor antagonists, with affinity comparable to that of melatonin, while 15 produced a noticeable reduction of GTPgS binding at MT2 receptor, thus being among the few inverse agonists described to date 44 . Audinot et al. have disclosed the compound S-70254 that selectively binds to the...

Norepinephrine reuptake inhibitors NRIs

The neurotransmitter norepinephrine is believed to play an important role in the etiology of depression. Approved antidepressants that belong to monoamine oxidase inhibitor (MAOI), TCA, SNRI, NRI and NDRI drug classes influence central norepinephrine function 17 . The development of selective NRI compounds has resulted in considerably fewer FDA approved drugs compared with the SSRI drug class 18 . No NRIs have been approved for treatment of depression in the U.S. and only reboxetine (8) has...

Obesity

The importance of CNS histaminergic systems in energy homeostasis is well established 17 . However, the potential role for H3R modulation in the treatment of obesity remains controversial in the absence of clinical validation. Conflicting data regarding the activity of H3 agonists and antagonists in rodent feeding models, along with the mildly obese phenotype of H3R knockout mice, have raised concerns regarding the utility of H3 antagonists in the treatment of obesity 29 . However, structurally...

Telbivudine

Country of origin Originator First introduction Introduced by Trade name CAS registry no Molecular weight Telbivudine is a p-L-thymidine nucleoside analog launched last year for the once-daily oral treatment of chronic hepatitis B virus (HBV) infection. It is the fourth nucleoside or nucleotide analog to be marketed for this indication. The previous drugs from this class include lamivudine, a deoxythiacytosine analog, adefovir, a nucleotide analog, and entecavir, a guanosine analog. Adefovir,...

Inhibitors Of Erk Pathway

Normal Cell U0126

Inhibitors of Tpl-2 (MKKK), MEK1 2 (MKK1 2) and ERK1 2 have been reported. Macrophages from Tpl-2 knockout mice lack ERK1 2 activation leading to loss of TNFa expression and are insensitive to LPS-induced endotoxin shock 9 . Inhibition of Tpl-2 and MEK1 2 produces potent anti-inflammatory effects in cellular and animal models. A series of naphthyridine- and quinoline-3-carbonitriles, compounds 1, 2 have been reported to be potent Tpl-2 inhibitors with IC50 values 2 and 19 nM, respectively 10,11...

SSAOVAP1 and inflammatory diseases

Inflammation is the first response of the immune system to infection or irritation. Leukocyte migration from the circulation into tissues is essential for this process. An inappropriate inflammatory response to a normally innocuous stimulus or to a false signal can result in local inflammation of an otherwise healthy tissue which can lead to disorders such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and respiratory diseases. In order to pass through the walls of the...

Pde11 Inhibitors

A recent study examined the role of all PDEs and their potential genetic contribution to major depression disorder (MDD). Interestingly, variants in PDE9A and PDE11A were found to be associated with the diagnosis of MDD, while variants in PDE1A and PDE11A were associated with remission on antidepressants. This highlights a potential role for PDE11A in the pathophysiology of MDD. Two recent PDE11 inhibitors, 19 (PDE11A IC50 0.7 nM PDE5 selectivity > 1000-fold) and 20 (PDE11A IC50 3.5 nM >...

Clinical trials of antagonists of MCP1CCR2

Three separate interventions against MCP-1 CCR2 have failed to provide clinical benefit in human patients suffering from rheumatoid arthritis. The diversity of modalities employed - an anti-MCP-1 antibody 46 , an anti-CCR2 antibody 47 , and a small molecule antagonist of CCR2 48 - suggest that the findings have revealed a redundant role for CCR2 in this disease process. A second small molecule antagonist (INCB-3284) is currently under investigation in rheumatoid arthritis, but no data have been...

Norepinephrine dopamine reuptake inhibitors NDRIs

After more than a decade of use, bupropion (24) is considered a safe and effective antidepressant, suitable for use as first-line treatment. In addition, it is approved for smoking cessation and seasonal affective disorder. It is also prescribed off-label to treat the sexual dysfunction induced by SSRIs. Bupropion is often referred to as an atypical antidepressant and has much lower affinity for the monoamine transporters compared with other monoamine reuptake inhibitors. The mechanism of...

Ranolazine

Country of origin Originator First introduction Introduced by Trade name CAS registry no Molecular weight CV Therapeutics Ranexa 95635-55-5 427.54 CV Therapeutics Ranexa 95635-55-5 427.54 Ranolazine is an orally available, extended release drug for the treatment of chronic angina in patients who have failed to respond to prior angina therapy. Chronic stable angina (CSA) is a common symptom of coronary artery disease wherein plaques in the coronary vasculature restrict blood flow to the heart,...

Nonclassical Estrogen Signaling

The classical model of E2 signaling involves binding to ERs within the cell nucleus, followed by receptor dimerization and interaction of ligand-bound receptor and coactivators with estrogen response elements (EREs) located in the promoter region of target genes. Measurable responses can be expected within hours of E2 exposure. In contrast to these gene regulatory effects, other rapid, and presumably nongenomic, effects of E2 are also observed. Since evidence for nongenomic pathways is...

Lipid Absorption And Mobilization

2.1 Microsomal triglyceride-transfer protein (MTP) Microsomal triglyceride-transfer protein (MTP) plays a pivotal role in the assembly of TG-rich apolipoprotein B-containing VLDL in the liver and chylomicrons in intestine. It is located within the lumen of the endoplasmic reticulum in hepatocytes and absorptive enterocytes. Its main function is to transfer lipids and cholesterol esters from the endoplasmic reticulum to lipo-protein particles for secretion into the circulation 8 . MTP is a...

Serotonin receptor modulators

Serotonin related compounds devoted to sleep disorders mainly act via 5-HT2A receptors. Compounds in clinical development reported with this mechanism of action are Eplivanserin, Pimavanserin, Pruvanserin, Volinanserin and APD-125. Eplivanserin (39) is a 5-HT2A antagonist initially developed for a broader spectrum of psychiatric disorders but that has been tested recently for insomnia. Within this latter indication, phase II studies showed benefits in sleep maintenance, but not in induction 9 ....

Alglucosidase Alfa

Country of origin Originator First introduction Introduced by Recombinant human protein Glucosidase 110 kDa Precursor CHO cell Genzyme Pompe disease is a lysosomal storage disorder that is characterized by a deficiency in the acid alpha-glucosidase enzyme that is responsible for the breakdown of glycogen to glucose. The lack of degradation results in the accumulation of glycogen in lysosomes, predominantly affecting cardiac and skeletal muscles. In cases of complete enzyme deficit, such as...

Ovarian Selective Serms

Uterine leiomyomas, or fibroids, are the most common type of solid tumors in adult women, clinically apparent in at least 25 of those of reproductive age 24-26 . Abnormal menstrual bleeding, pelvic pain, and infertility are the most commonly experienced symptoms in these women. Uterine fibroids are the leading cause of hysterectomies performed in the United States, accounting for over 200,000 of these procedures each year. Other invasive surgical interventions for the treatment of uterine...

Ra Selective Serms

The discovery of a second estrogen receptor, ERp, in 1996 has generated considerable interest in the development of sub-type selective SERMs for ERa and ERp, including a series of ligands that are highly selective for ERa such as flavanone 10 36 , dihydrobenzoxathiin 11 37 , and chromane 12 38 . Flavanoid 10 was found to be gt 50-fold selective for ERa in binding. The selectivity was postulated to lie in the differential interaction of the carbonyl moiety of 10 with the two residues which vary...

Gpr40 Family

Function, and suggests a key role for GPR40 in the development of the metabolic syndrome in obesity. Since the putative natural ligands for the GPR40 receptor are LCFAs, it comes as no surprise to find that the majority of synthetic agonists reported to date are lipophilic carboxylic acids. Thus, GPR40 agonists 14-18 have all been reported to have EC50s of 20 nM or less in various patent applications 63-67 . Recently, the first two papers detailing the SAR associated with a series of GPR40...