References

Muller, Farmaco, 2001, 56, 77. 2 B. Pavan and A. P. Ijzerman, Biochem. Pharmacol., 1998, 56, 1625. 3 D. Zeng, R. Polosa, I. Biaggioni and L. Belardinelli, in Asthma Modern Therapeutic Targets (eds R. Polosa and S. T. Holgate), Clinical Publishing, Oxford, UK, 2007, pp. 1-13. 4 R. A. Brown, D. Spina and C. P. Page, Br. J. Pharmacol, 2008, 153, S446. 5 M. van der Berge, M. N. Hylkema, M. Versluis and D. S. Postma, Drugs RD, 2007, 8,13. 6 A. G. Driver, C. A. Kukoly, S. Ali and S. J....

Rationale For Selective Targeting Of Jak3 In Inflammatory Diseases

The JAK signal transducer and activator of transcription (STAT) signaling pathway has been extensively studied but specific details regarding cascade regulation remain unelucidated 6 . In cells, JAK3 associates with cytokine receptors, which homodimerize and heterodimerize upon binding of the ligand. JAK3 binds specifically to the gamma common chain (gc) that is shared by the cytokine receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21 5 . Upon ligand binding, JAK3 becomes...

Introduction

Numerous attempts have been made toward the design of isozyme-selective NOS inhibitors targeting both the L-arginine and BH4-binding sites. Early inhibitors were based on modifications of mono- and dipeptides, with subsequent inhibitor design and synthesis utilizing co-crystal structures of all NOS isozymes. Several review articles covering progress toward the development of selective nNOS inhibitor syntheses 23,24 , selective iNOS inhibitor syntheses 25 , and computational studies 26 have...

Pain

CB2 agonists such as GW405833 (1) have been found to be efficacious in several preclinical models for inflammatory, neuropathic, and postoperative pain. GW405833 is a selective CB2 agonist with a binding affinity of 3.92 +1.58 nM for human CB2 versus 4772 71676 nM for CB1 (> 1,000-fold selectivity) 9 . Selectivity for CB2 was diminished for rat receptors, with only a 78-fold selectivity ratio for CB2 over rat CB1. Functionally, this compound appeared to be a partial agonist at the human CB2...

Inhibitors Of The Hedgehog Pathway

A recent report described the semi-synthesis of the D-homocyclopa-mine analog 2 (IPI-269609 IPI-609) from cyclopamine through an oxidation cyclopropanation ring expansion sequence 28 . Compound 2 was then further functionalized through acylation, reductive amination, or direct alkylation. Hh pathway inhibition was assessed in murine progenitor C3H10T1 2 cells. When the Hh pathway is active, these cells differentiate into osteoblasts and produce high levels of alkaline phosphatase (AP). A...

The Search For Partial Agonists Cytisine As A Key Starting Point

Early in our drug discovery program, we sought information on the level of partial agonist efficacy that would be effective for smoking cessation and any available chemical tools to distinguish a partial agonist from the effects of the full agonist nicotine. We required a substance that would displace nicotine from its neuronal binding site and reduce the subjective experience of nicotine administration by simultaneously attenuating the dopaminergic response to nicotine. Evidence for partial...

Preclinical Isozymeselective Pi3k Inhibitors

A number of compounds that exhibit PI3K isozyme selectivity have been disclosed, which have yet to enter the clinic. Generally, these pre-clinical compounds are selectively potent for a sub-set of the PI3K isozymes (i.e., they are not specific inhibitors), but for clarity in this review, they will be classified by the isozyme which is most potently inhibited. TGX-221 (18) - Compound 18 (Figure 5) (PI3KIC50 > 5000, 5-10, > 3500, 100-200 nM for a, b, g, d, respectively) is the lead compound...

The Emergence of GPR119 Agonists as Anti Diabetic Agents

Leonard Discovery and Characteristics of GPR119 3.1 Proposed endogenous regulators of GPR119 3.2 GPR119 regulation of insulin release 3.3 GPR119 regulation of GLP-1 and GIP release GPR119 Agonists Medicinal Chemistry 4.1 Six-membered heterocyclic ring-based agonists 4.2 Five-membered heterocyclic ring-based agonists Clinical Trial Status and Future Prospects

Selective iNOS inhibitors

Inducible NOS has been implicated in a number of inflammatory diseases such as septic shock, multiple sclerosis, rheumatoid and osteoarthritis, ulcerative colitis, and asthma. Not surprisingly, many research institutions have developed programs to design inhibitors of iNOS. In addition to potency, selectivity against the other two isoforms, especially eNOS, is required since they are important in normal physiology. Selective inhibitors of iNOS have been reviewed previously 25 . Early inhibitors...

Pharmacology

Receptor binding studies 55,58 demonstrated that varenicline (1) has high affinity only for the a4b2 neuronal nicotinic receptor subtype in rat and human cortex (K 0.1-0.4 nM). Varenicline did not bind with significant affinity to various other neurotransmitter receptors and transporters, enzymes, modulatory binding sites, and ion channels, in membranes derived from relevant tissues and cell lines (K values > 1,000 nM). In vitro functional patch clamp studies in Xenopus oocytes and HEK cells...

A2a Adenosine Receptor Agonists Cgs21680 UK371104 AND GW328276

Activation of A2A AR has the following anti-inflammatory effects on various cell types inhibition of the release of histamine and tryptase from mast cells 33 and reduction of chemotaxis, in addition to activation degranulation of neutrophils 19,34,35 . Activation of A2A AR also increases the production of anti-inflammatory IL-10 from monocytes and macrophages 36 . Therefore, various A2A AR agonists have been evaluated in animal models of asthma and have even advanced into clinical trials 37 ....

In Vivo Efficacy Of Partial Agonists

The in vivo efficacy of analogs was determined by measuring effects on mesolimbic DATO, which reflects a change in postmortem tissue concentration ratios of DA and its metabolites in the rat nucleus accumbens. Compounds were evaluated subcutaneously (s.c.) and, if active, were re-examined after oral administration. In this assay, nicotine (2) produces a maximal DATO response at 1 mg kg s.c. of 180 of control levels. The partial agonist activity of an agent alone was determined by comparison of...

Gpr119 Agonists Medicinal Chemistry

4.1 Six-membered heterocyclic ring-based agonists Following a cyclase-based high throughput screening (HTS) campaign, pyrimidine 9 was identified as an inverse agonist of hGPR119 (IC50 84 nM) 22 . In structure activity relationship (SAR) studies related to 9, the trifluoromethyl pyrazole motif was replaced with a series of aryl ethers leading to the identification of agonists 10 (EC50 1 p.M) and 11 (EC50 1.7 mM). Further extensive parallel SAR work led to the identification of multiple...

A2b Adenosine Receptor Antagonists Cvt6883 MRE 2029F20 LAS38096 And Osip339391

There is substantial evidence to indicate that A2B ARs contribute to airway inflammation in asthma and that a compound specifically inhibiting the A2B AR may have beneficial effects 46-49 . Activation of A2B ARs on human bronchial smooth muscle cells (BSMCs) has been shown to induce the release of the inflammatory cytokines IL-6 and monocytic chemotactic protein-1 50 . A2B AR activation on human bronchial epithelial cells (HBECs) releases IL-19, which in turn activates human monocytes to induce...

V1b Receptor Antagonists

SSR149415 (14), a potent, selective V1b receptor antagonist was progressed to phase II trials for major depression 48,49 but appears to have been discontinued 50 . The compound was extensively studied in a range of anxiety and depression models 3 . For example, SSR149415 was recently demonstrated to have efficacy similar to that of imipramine in the rat olfactory bulbectomy-induced (OBX) hyperactivity depression model 35 . The compound (at 10 and 30mg kg i.p.) completely inhibited OBX-induced...

The Biology Of Gpr119

3.1 Proposed endogenous regulators of GPR119 Lysophosphatidylcholine (LPC, 1) was the first proposed endogenous ligand for GPR119, based on its ability to stimulate glucose-dependent insulin release and increase cAMP in GPR119-transfected cells 6 . However, subsequent studies showed that the efficacy of 1 is poor, relative to other GPR119 modulators 10-11 . 1 also mediates insulin release in insulinoma cell lines that lack GPR119, shedding further doubt on the likelihood that this lipid is a...

Discovery Of The Bicyclic Benzazepine Core

The weak in vitro and in vivo responses of non-pyridone cytisine derivatives (Figure 7) drove our expanded search for alternative structural scaffolds targeting improved potency and partial agonist activity (Figure 8). We synthesized various reasonable assemblies of the critical functional groups found in many natural nicotinic agents, probing alternative locations and orientations of necessary functionality. Many of these approaches proved disappointing, since they did not provide improvements...

A1 Adenosine Receptor Antagonists L971 Bg9928 Fk838 And Wrc0571

Activation of A1 adenosine receptors (ARs) may play a role in mucus production by human epithelial cells 16 , human bronchial smooth muscle contraction 17 , and neutrophil chemotaxis 18,19 . However, activation of ARs on macrophages has the following effects inhibits the production of several pro-inflammatory cytokines, including tumor necrosis factor-a (TNF-a), IL-6, and IL-8, and enhances the release of the anti-inflammatory cytokine, IL-10 20-22 . Several compounds from different classes of...

Effects Of Aliskiren In Disease Models

As indicated previously, dTGR, which express the human genes for renin and angiotensinogen 15 , are very responsive to inhibition with a human renin inhibitor. Single oral dosing of 1 to chronically catheterized dTGR resulted in a dose-dependent, rapid and marked lowering of MAP with a long duration of action 71 . The first evidence that 1 exhibits potent cardio-renoprotective effects was determined in dTGR after chronic treatment 16 . Left ventricular hypertrophy associated with hypertension...

HCV NS34A protease inhibitors

Proof-of-concept for NS3 protease inhibitors as antiviral agents with potential for the treatment of HCV was provided by clinical studies conducted with BILN-2061 1 . This compound was administered to patients infected with genotype 1 virus using a dosing regimen of 200 mg BID for 2 consecutive days, which produced a greater than 2-3 log10 reduction in plasma HCV RNA in all patients treated 40 . Since this seminal study, a significant number of protease inhibitors have progressed into clinical...

Smallmolecule inhibitors of Ab aggregation 221 5cyoinositol

Recent in vitro studies with scyllo-inositol 1 have shown that it can interact with Ab42 peptide promoting a conformational change from random coil to b-sheet structure and stabilized it in small, nonfibrillar complexes, blocking fibril formation 22 . These stabilized complexes were significantly less toxic to neuronal cell lines and primary neuronal cultures than untreated Ab42 or chiro-inositol-treated Ab42 22 . Moreover, in in vivo studies in the TgCRND8 mouse model of AD, it was shown that...

Clinically Investigated Panactive Class I Pi3k Inhibitors

SF1126 3 - Although 1 emerged as an invaluable tool in establishing the biological role of PI3K in human cancer, poor physicochemical properties and short plasma half-life made it unsuitable for further development. Attempts to improve the pharmacokinetic profile of 1 have led to the development of a water soluble prodrug 3 Figure 3 , currently in phase I clinical trials for cancer. Prodrug 3 is a peptide conjugate of 1 that specifically targets cell-surface integrins within the tumor. Although...

V1a Receptor Antagonists

Srx251 Chemical Structure

Relcovaptan SR49059, 1 has shown clinical efficacy for indications modulated by the peripheral Via receptor including Raynaud's syndrome, dysmenorrhea and preterm labour 5 , but its development has been interrupted as a result of possible interference with cytochrome P450 32 . The development of OPC-21268 2 , another Via receptor antagonist, has been discontinued in Europe and in the United States 33 . Nevertheless, the positive proof-of-concept studies with relcovaptan have triggered the...