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. Probucol...
Possession Of Facts
There are two major categories of facts that form a basis for medicinal chemist's choices Table 1 . One is related to our understanding of how the human body, an extremely complex system, operates at all levels - molecular, cellular, organ and whole organism. The other has to do with our ability to know precisely what chemical compounds actually do in the body. Concerning the former, in spite of accumulating a significant body of information about it, we are very far from the complete...
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,...
The Acyl Sulfonamide Antiproliferatives
In 2004, Lilly reported 8 the discovery and SAR of acylsulfonamide antiproliferative ASAP compounds of general structure 4. Subsequently, the activity of a second series 5 of thiophenyl acylsulfonamides was reported, and the compounds showed cellular activity comparable to the parent biaryl series Fig. 2 9 . The two initial leads 4a and 4b, one unsubstituted in the sulfonyl phenyl ring, and the other mono-substituted by chlorine in the ara-position of the same ring, were identified in...
AMINERGIC RECEPTOR MODULATORS 41 5HT2CR agonists
The 5-HT2C receptor 5HT2CR was identified in 1986 and is widely expressed in the CNS 93 . Several lines of evidence support a role for this receptor in body weight regulation. KO mice exhibit a phenotype characterized by increased body weight relative to wild-type littermates average of 13 increase , increased food intake, and a significantly greater percentage of adipose tissue 48 increase 94 . The non-selective 5HT2CR agonist mCPP was found to reduce food intake in wild-type mice, but not in...
Introduction Nev
In 2005, the FDA approved three new small molecules for cancer indications Fig. 1 nelarabine 1 Arranon , GlaxoSmithKline for acute lymphoblastic leukemia 1 , sorafenib 2 Nexavar , Bayer for advanced renal cell carcinoma 2 , and lenalido-mide 3 Revlimid , Celgene for treatment of patients with transfusion-dependent anemia due to myelodysplastic syndrome 3 . Each drug has a different mechanism of action MOA . Nelarabine is a prodrug of the antimetabolite ara-G, sorafenib inhibits several kinases,...
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...
Sarscov 3clpro Inhibitors
Proteolytic processing of the coronavirus replicase polyproteins is essential for ongoing viral RNA synthesis. Therefore, the SARS-CoV proteases are attractive targets for the development of antiviral drugs to reduce viral replication and pathogenicity. The structure and activity of the coronavirus 3CLpro has already been elucidated and the design of inhibitors to 3CLpro as therapeutics has been proposed 9,10 . SARS-CoV 3CLpro has three domains I residues 8-101 , II residues 102-184 , and III...
Prodrugs With Other Benefits
Recent reports on inventive prodrug approaches targeting other benefits beyond improved oral bioavailability and selective tissue delivery are described in this section. Although sustained release of an active agent has hitherto been solely the subject of drug formulation studies, efforts toward prolonging plasma half-life using prodrugs have recently been reported. A polyserine-naltrexone conjugate 58, in a 10 1 ratio of serine to naltrexone , when administered to rats orally, afforded a...
Toxicophore In Trovafloxacin
moiety in zafirlukast 1 to give the glutathione adduct 2 is a noteworthy extension to the SAR of the 3-methylindole activation pathway 30 . The thiophene fragment has similarly been associated with metabolic activation in a number of publications Table 2 however, there has been less evidence for activation of benzothiophene. A recent paper highlights metabolic activation of 2-substituted benzothiophenes 31 . Metabolism of the benzothiophene moiety in the 5-lipoxygenase inhibitor zileuton 3 has...
Miscellaneous
Recent patent applications have described novel chemical structures that do not fit into either of the above categories. Benzimidazoles e.g. 30 40 and quinazolines e.g. 31 have been claimed as GKAs 41 . The vital role of GK in glucose homeostasis has been established for some time. Developments over the last decade, including the discovery of the regulatory function of GKRP, identification of maturity-onset diabetes of the young MODY-2- , permanent neonatal diabetes PNDM- and Persistent...
Diamides blockers
Compound 8, IC50 0.15 mM against Nav1.7, was recently identified via HTS screening in a functional assay and has been extensively profiled 41,42 . It was nonselective when tested against Nav1.2, Nav1.5 and Nav1.7 in EP. This compound demonstrated both voltage- and use-dependence and blocked TTXr currents in dissociated mouse DRGs with an IC50 0.025 mM. It demonstrated activity in the rat formalin assay with either intradermal administration or i.v. administration. Poor PK properties oral...
Conclusion Tal
The diversity of chemical structures that have been reported 46 to be inhibitors of VCAM-1 expression suggests that there may be numerous upstream molecular targets regulating VCAM-1 expression with which different inhibitors interact. Antioxidants may interact with one target and chalcones with another. Even the antioxidants that have shown inhibition on VCAM-1 expression may interact with different targets of the VCAM-1 expression pathway, since PDTC, AGI-1067, and carvedilol 99 are different...
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...
SARSCoV 3CLpro inhibitors from screening
Extensive screening has been carried out in an effort to find structural leads against SARS-CoV 3CLpro from existing drugs. A major advantage is that approved drugs with minimal modifications may have the possibility of gaining accelerated approval by US Food and Drug Administration. It was reported that Kaletra, a mixture of protease inhibitors - Lopinavir and Ritonavir, approved for treating HIV in 2000, shows some effectiveness against the SARS virus 30 . Based on this observation, the...
Estrogens
There is a growing interest in the actions of estrogens as neuroprotectants against neurodegenerative diseases and acute brain damage caused by stroke. Estrogens exert their neuroprotective effects predominantly through antioxidant effects of steroids and attenuation of NMDA-receptor activation 98,99 . In in vivo studies, the neuroprotective effects of estrogens have been demonstrated in all acute cerebral ischemia scenarios and it has been shown that estrogens could have a longer therapeutic...
Conclusion Jig
A decade after research into peptidomimetic renin inhibitors lost favor, several classes of non-peptidic inhibitors, including aliskiren, have been discovered. Potent examples of these classes contain basic amines that interact with the catalytic as-partates and structural elements that occupy Ss3p. Structure-based drug design has played an influential role in the discovery of these compounds. 2 G. Cohuet and H. Struijker-Boudier, Pharmacol. Ther. 2006, in press. 3 B. B. Scott, G. McGeehan and...
Conclusion Jll
Several classes of compounds that are potent and selective 11p-HSD1 inhibitors have been identified. Representatives from the thiazole, triazole, and amide series have demonstrated activity in rodent models of diabetes and metabolic syndrome. However, no significant clinical data has been reported, and only two compounds AMG-211 and INCB-13739, structures unknown 126 are reported to be in clinical trials. Animal studies have suggested that 11p-HSD1 inhibition is a potential treatment for...
Indole acetic acid derivatives 1
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...
Udenafil Erectile Dysfunction [111115
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...
Azoles
Azole antifungal agents include imidazole and triazole derivatives that prevent the synthesis of ergosterol, a major component of fungal membranes, by inhibiting the cytochrome P-450-dependent enzyme 14a-lanosterol demethylase CYP51 10,11 . This enzyme contains an iron protoporphyrin unit located in its active site, which catalyzes the oxidative removal of the 14a-methyl group of lanosterol, by typical monooxygenase activity 12 . Azoles bind to the iron of the porphyrin 13 and cause the...
Sns595
SNS-595 6, SPC-595 formerly AG-7352 is a 1,8-disubstituted naphthyridine whose discovery and SAR were originally reported by Dainippon Pharmaceuticals 13,14 . The discovery came from screening antibacterial quinolines for antitumor activity, and finding that 1,8-naphthyridines possess cytotoxic activity against murine P388 leukemia. The rationale behind the screening for cytotoxic activity in tumors rather than bacteria was that the quinolone antibacterials are known to inhibit topoisomerase II...
Noncovalent SARSCoV 3CLpro inhibitors
Side effects and toxicity often arise with covalently bonded inhibitors which hinder or prevent their development as useful drug therapies 19,20 . To avoid such pitfalls, it is often desirable to design and develop non-covalent or reversible inhibitors as therapeutic agents. A series of synthetic small molecule, non-covalent inhibitors of SARS-CoV 3CLpro was published in 2004 21 . These investigators previously reported that keto-glutamine analogues with the phthalhydrazido group at a-position...
Selective PPARy modulators
In attempts to circumvent the previously described limitations of PPARg full agonists, zealous efforts are underway to identify and characterize selective PPARg modulators SPPARgMs or partial agonists that retain desirable efficacy and exhibit superior tolerability, an endeavor further complicated by the lack of a consistent definition for SPPARgMs and a precise understanding of the molecular mechanisms by which PPARg full agonists exert their deleterious effects. In principle, however, a...
Avian influenza vaccine
Traditionally, vaccination has been the principal approach to protecting individuals against influenza. Currently, no influenza A H5N1 vaccine is available although several candidate vaccines are being developed. Preliminary data suggest that either higher concentrations of antigens than used in seasonal influenza vaccines and or addition of adjuvants to these vaccines will be necessary to induce protective responses 8 . Gearing production, to rapidly make necessary quantities, of such a...
Future Outlook
It is with unprecedented rapidity that a basic understanding of SARS-CoV life cycle has been achieved. Already, a number of targets including SARS-CoV 3CLpro and SARS-CoV PLpro appear very promising for anti-SARS-CoV chemotherapy. Since the global outbreak of SARS ended in 2003, only a small number of cases of SARS associated with laboratory exposures have been reported. However, with the identification of Chinese horseshoe bats as an animal reservoir for SARS-CoV, the potential danger of the...
SSRI 5HT1D antagonism
The 5-HT1D receptor functions as an autoreceptor controlling the release of 5-HT from nerve terminals. Therefore a drug with a combination of SERT inhibition and 5-HT1D antagonism may also be of interest as a more rapid-acting antidepressant. Compound 12 was identified as a potent SSRI K 0.11 nM that also exhibits 5-HT1D affinity K 56 nM , with less affinity for the 5-HT1B receptor K 281 nM 25 . In microdialysis studies in guinea pigs 12 increased hypothalamic 5-HT levels as high as 300 of...
Other PPAR dual and pan agonists
Considerable effort has been expended to identify insulin sensitizers that retain useful activity on one or both of the other two PPAR isoforms. These include a series of PPARa 8 dual agonists i.e. 28 , though no in vivo data were provided 78 . The indole acetic acid 29 was a potent PPARa y 8 pan agonist with excellent efficacy in a rodent diabetes model 79,80 . A series of pan agonists with comparable receptor potencies were reported 30 showed significant activity in the db db model 81 ....
Ispinesib and related compounds
2.1.1. 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 gt 70,000-fold selective for KSP versus other members of the...
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 gt 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 weak...
Pyrroles
Sudoterb belongs to a class of compounds known as pyrroles, which are plant alkaloids. Sudoterb has been reported to have potent anti-TB activity in vitro and in vivo. In vitro, sudoterb has bactericidal activity similar to isoniazid and is synergistic with rifampin. The combination of sudoterb with isoniazid, rifampin, and pyrazinamide led to complete sterilization of both sensitive and MDR-TB strains in mice within two months, and in combination with rifampin and pyrazin-amide, cured TB in...
Subtype selective blockers
There have been a several reports of selective agents in the recent patent literature. In addition, in a press release Vertex has stated that they have entered into a deal with GSK to develop a selective Na channel blocker for neuropathic pain. Biarylpyridine derivatives 6 have been claimed to be at least 5-fold selective for Nav1.8 over the TTXs currents endogenously expressed in the SH-SY5Y neuroblastoma cell line 37 . Ambroxol 7, a secretolytic compound on the market for the treatment of...
Saligenins
The saligenin head group has been used with success to prepare long acting b2-adrenoceptor agonists with salmeterol playing a prominent role as a benchmark compound. In this connection, the combination agent AdvairTM salmeterol and fluticasone is currently in third place globally in terms of sales, demonstrating the success of this approach. A common tactic employed to initiate research in this area has been to emulate salmeterol and modify its scaffold to improve the duration of action of the...
Phenoxy acetic acid derivatives
Several research groups have independently reported on phenoxyacetic acid derivatives as antagonists of the CRTH2 receptor. Compound 53 exemplifies a family of 2-cycloalkyl phenoxyacetic acid antagonists of CRTH2 86 . This compound was reported to inhibit binding of 3H -PGD2 to the CRTH2 receptor in membranes from K562 or CHO cells with a K of 21 nM. In addition, compound 53 was reported to have an IC50 value of 139 nM in a cAMP assay using CHO cells expressing the CRTH2 receptor. Researchers...
SNRIs
Venlafaxine has become mainline therapy for major depressive disorder MDD and has been shown to have a higher remission rate than the SSRIs 11 . Duloxetine was launched in the U.S. in 2004 and is reported to have more balanced affinities at the serotonin transporter SERT and NET 12 . The next SNRI to be launched is likely to be desvenlafaxine 1 succinate, which is the succinate salt of an active metabolite of venlafaxine, and is currently undergoing FDA review. The SNRI F-98214-TA, 2, is a...
Agents 1
Y. Sudhakara Babu, Pooran Chand and Pravin L. Kotian BioCryst Pharmaceuticals, Inc., 2190Parkway Lake Dr., Birmingham, AL 35244, USA 2. Inhibitors based upon six-membered heterocycles 288 2.1. Pyranose-based inhibitors 288 2.2. Cyclohexene-based inhibitors 290 2.3. Benzene-based inhibitors 290 3. Inhibitors based on five-membered ring structures 291 3.1. Furanose-based compounds 291 3.2. Cyclopentane-based inhibitors 292 3.3. Pyrrolidine-based inhibitors 293 4. Drugs approved or under clinical...
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,...
General themes
The generic pathways by which structural fragments may link to adverse outcomes are summarized in Fig. 1. Of particular note are idiosyncratic drug responses which Fig. 1. Pathways linking toxicophores to adverse outcome. Fig. 1. Pathways linking toxicophores to adverse outcome. often remain undetected until late stage clinical trials or post marketing when a large enough patient population is exposed to the drug to detect such a response. Such reactions are, by their very nature, difficult to...
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, transcription...
PLpro INHIBITORS
Numerous studies on the structural and mechanistic aspects of SARS-CoV 3CLpro have provided multiple avenues for structure-based design of antiviral compounds targeted against the 3CLpro active site 9,16,44,45 . On the other hand, structure-based design against the membrane-associated PLpro enzyme, either from SARS-CoV or related coronaviruses, has remained elusive due to lack of structural information. Unlike many coronaviruses that encode two PLpro paralogs PLP1 or PLP2 , SARS-CoV has a...
Small molecule antagonists
In the last decade there has been considerable interest in overcoming the shortcomings of the first generation peptide antagonists, by identifying orally active non-peptide oxytocin antagonists with a higher degree of selectivity towards the vaso-pressin receptors V1a, V1b, V2 . As a result, several templates have been investigated as potential selective oxytocin antagonists 8-10 . Reflecting the close structural similarity between the oxytocin and vasopressin receptors especially V1a, most of...
Inhalation Products
The advancements in design and control of high-performance inhalation products are complemented by the advancements in the tools necessary for understanding drugs for pulmonary drug delivery. At the early stages of development, the pulmonary ADME of compounds can be explored rapidly and inexpensively by the use of custom delivery systems for small and large animal species. Precise animal experiments are often able to accurately predict development paths. However, the efforts in inhalation...
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...
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...
Exenatide Antidiabetic [3741
Exenatide is the first drug in a new class of anti-diabetics known as the incretin mimetics, and it is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who are taking metformin, a sulfonylurea, or both, but have not achieved adequate glycemic control. Exenatide is a functional analog of the human incretin Glucagon-Like Peptide-1 GLP-1 . GLP-1 is naturally released from cells in the GI tract in response to food intake and acts on its receptor on...
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...
SSRI 5HT1A antagonism
The dual SSRI-5-HT1A antagonist Lu 36-274 7, 5-HT1A K 4.5 nM, SERT IC50 6nM combines the 5-HT1A binding properties of a phenylpiperazine moiety with the SERT inhibitory ability of a 3-indolyl-alkylamine moiety 20 . Lu 36-275 is selective versus D2 dopaminergic receptors K 430 nM and to lesser degree versus a1 adrenoreceptors K 110 nM . Rat cortical 5-HT levels were increased to 500 of control after an acute dose of 16mg kg, sc. In the schedule-induced polydipsia SIP model Lu 36-274 reduced...
Oxytocin Antagonists and Agonists
GlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK 2. Oxytocin antagonists 410 2.1. Peptide antagonists 411 2.2. Small molecule antagonists 412 3.2. Small molecule agonists 417 4. Conclusions 419 References 419
Strategic Directions
Overall, formation of reactive metabolites and subsequent covalent modification of macromolecules is a potential liability in drug discovery and a potential source of attrition. However, it must be emphasized that in most cases there is no conclusive evidence linking formation of reactive metabolites and idiosyncratic toxicity. Indeed, for some of the examples presented above alternative mechanisms have been proposed to explain the toxicity, which did not involve bioactivation. Nevertheless,...
Nuclear Hormone Receptor Modulators for the Treatment of Diabetes and
Peter T. Meinke, Harold B. Wood and Jason W. Szewczyk Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA 2.4. PPARa y dual agonists 105 2.5. Other PPAR dual and pan agonists 107 2.6. Selective PPARy modulators 108 4.1. LXR subtype selective agonists 114 4.2. Current patent literature 115 6. Conclusion 118 References 118