Sterol biosynthesis pathway inhibitors

One promising area of recent research on Chagas disease is sterol biosynthesis inhibition 5 . Like Leishmania, T. cruzi requires specific sterols for cell viability and proliferation in all stages of its life cycle. Consequently, several enzymes in the ergosterol biosynthesis pathway have been validated as targets. Posaconazole (59), a selective cytochrome P450-dependent C14a sterol demethylase (CYP51) inhibitor, has shown para-sitological cure in murine models of both acute and chronic stages...

Unbound compound concentrations and the free drug hypothesis

Based on the described neuroanatomy, the three key matrices for evaluating compound concentrations to determine the extent and or rate of CNS penetration are blood, CSF, and brain tissue. Due to the nearly universal analysis of plasma to determine systemic concentrations of small molecules, total plasma compound concentration (Cp) will henceforth be substituted for total blood concentration, which is the product of Cp and compound blood-to-plasma ratio. 2.2.1 Intercompartmental compound...

Noncompetitive inhibitors

Compounds that strongly chelate iron have been known for many years to stabilize HIF-1a as well as upregulate proteins involved in red blood cell production erythropoietin (EPO), angiogenesis, vascular endothelial growth factor (VEGF), and iron transport. Some, but not all, of the pharmacological actions of iron chelators are produced by inhibition of PHD enzymes resulting in elevation of cellular HIF content. The action of selected iron chelators as they relate to PHD inhibition are briefly...

National Cancer Institute Next Program

Purpose The NCI Experimental Therapeutics (NExT) program is designed to assist investigators in bench to bedside translation of novel anticancer therapeutic interventions, synthetic, natural product, or biologic, arising from academic, industrial, or government entities. The program provides the resources for selected discovery tasks, comprehensive pre-clinical IND-enabling tasks, and biomarker development for Phase 0 clinical studies. The tasks are completed by NCI staff and contractors,...

R

Figure 3 The catalytic mechanism for oxidative demethylation by LSD1. 30 mM 74 , which is comparable to substrate Km values for other histone-modifying enzymes. H3K4me2 is a transcription-activating chromatin mark at gene promoters and demethylation of this mark prevents expression of tumor suppressor genes important in human cancer 73 . Thus, LSD1 is emerging as an important new target for the development of specific inhibitors that could become a new class of antitumor agents 84 . The X-ray...

Tankyrase Inhibition As A Strategy For WntpCatenin Pathway Modulation

The Wnt p-catenin pathway is frequently inappropriately activated in many tumors and, consequently, has long been a target for therapeutic intervention. Inhibiting tankyrase disrupts the Wnt p-catenin pathway, suggesting that this may be a new approach for targeting the pathway. Two independent groups identified small-molecule inhibitors using cellular Wnt p-catenin pathway reporter assays 55,56 . Compounds 39 and 40 inhibited Wnt signaling with IC50 180 and 350 nM, respectively, and 39...

Synthetic Lethality Of Inhibiting Parp1 And Parp2 In Brca Mutant Tumors

Recently, data has emerged suggesting that targeting more than one DNA repair pathway in tumor cells could induce synthetic lethality, which is a phenomenon whereby deletion of a single gene or inhibition of the gene product is compatible with viability, but two simultaneous deletions, mutations, and or inhibition are lethal 11-13 . Specifically, PARPi selectively kill breast cancer type 1 susceptibility protein (BRCA)-1- or BRCA-2-deficient tumor cells while, in contrast, PARPi have minimal...

Monotherapy in BRCA mutant tumors

Olaparib is the first PARPi to show antitumor activity when administered as monotherapy, confirming the preclinical findings of synthetic lethality in BRCA-1 and BRCA-2 mutant tumors. The results of a Phase I study have recently been reported 42 , in patients carrying BRCA-1 and BRCA-2 mutations where clinical benefit was observed in 63 of patients following doses up to 600 mg bid. Olaparib was administered at a dose of 400 mg bid in two Phase II studies involving BRCA-1 and BRCA-2 mutation...

Application To Tumors With Other Dna Damage Repair Deficiencies

Besides BRCA-deficient cells being sensitive to PARPi, efforts have been undertaken to extend the utility of PARPi to cancers containing other genetic defects. Given the role of BRCA-1 and BRCA-2 in the DNA repair by HR, the effects of deficiencies in other proteins involved in HR were investigated 13 . Deficiencies of RAD51, ATR, ATM, CHK1, FANCD2, FANCA, and others were shown to cause a similar sensitivity to PARPi. Interestingly, mutations in the ATM gene have been found in patients with...

Nihraid Program

Purpose The NIH-RAID (Rapid Access to Interventional Development) program was developed to provide core pre-clinical drug development services as part of the NIH Roadmap bench to bedside translational medicine initiative. NIH-RAID provides a path forward to clinical trials for academics, non-profits, and small businesses, and is meant to serve as a bridge to future funding. The program potentially encompasses all therapeutic areas, and is currently administered through the National Institute of...

National Cancer Institute Cbc Program

Purpose The NCI Chemical Biology Consortium (CBC) is a developing biotech-like venture designed to assist investigators in the development of novel cancer therapeutics. The program goal is to increase the number of early-stage drug candidates entering the NCI development pipeline by establishing a drug discovery consortium on the scale of a small biotech company. The focus of the group will be on high-risk, underrepresented areas, and in significantly advancing the discovery of novel agents...

Antagonists

The most compelling evidence for TLR activation associated with self-nucleic acids is with the overproduction of type I IFN in patients with SLE, scleroderma, and Sjogren's syndrome. Antibody against autologous DNA is seen in these diseases, and studies using purified patient-derived IgG mixed with apoptotic or necrotic cell debris show activation of pDCs 71 . These cell populations are active in production of interferon and autoantibody, which are elevated in this disease. Activation is...

Preclinical Jak2 Inhibitors

Similar activity has been reported for WP1066 (8), a tyrphostin analog optimized from AG490. The biochemical potency and kinase selectivity profile of this compound has not been reported, but compound 8 blocked the proliferation of JAK2V617F-bearing HEL cells with an IC50 of 2.3 jmM and had significant ex vivo activity in a clonogenic assay utilizing PBMCs isolated from JAK2V617F-positive PV patients 38 . Butanone derivative Z3 (9) was identified from a library of 20,000 compounds by DOCK, a...

Info

Sponsored by the Division of Medicinal Chemistry of the American Chemical Society Neuroscience Discovery Chemistry Bristol-Myers Squibb R& D Wallingford, CT, United States ROBICHAUD STAMFORD BARRISH WEINSTEIN PRIMEAU LOWE DESAI MCALPINE Amsterdam Boston Heidelberg London New York Oxford Paris San Diego San Francisco Singapore Sydney Tokyo ACADEMIC Academic Press is an imprint of Elsevier PRESS Academic Press is an imprint of Elsevier Linacre House, Jordan Hill, Oxford OX2 8DP, UK 84...

Fluorine As A Bioisostere

The use of fluorine to modulate properties including potency, selectivity, pharmacokinetics, and toxicity has have been highlighted. Fluorine has also been suggested as a potential bioisosteric replacement for a number of functional groups, examples of which are presented in the final section. Gamma-aminobutryic acid (GABA) (53) is the major inhibitory neurotransmitter in the CNS. When GABA levels in the brain fall below a threshold level, convulsions begin. Since GABA does not cross the...

In re 318 Patent Infringement Litigation galantamine

Case History In an attempt to protect their galantamine franchise from generic competition, Janssen Pharmaceutica N.V., Janssen L.P., and Synaptech, Inc. (collectively Janssen) sued various generic pharmaceutical manufacturers for infringing upon Claims 1 and 4 of U.S. Patent No. 4,663,318 ('318). The claims were drawn to methods of treating Alzheimer's disease with galantamine or salts thereof. At trial, the generic manufacturers conceded that they infringed Claims 1 and 4 of the '318 patent...

Discovery of clinical candidates

A series of phthalazinone PARPi has been developed from micromolar screening hits 16 . Initial optimization identified 4-benzyl derivative 2, which was quickly optimized to meto-derived analog 3 (PARP-1 IC50 770 and 20 nM, respectively). Constraint, as with imide 4, improved activity (IC50 12 nM), although 4 displayed only modest cellular activity (PF50 1.74, where PF50 is a measure of the potentiation of methyl metha-nesulfonate (MMS) defined as GI50(MMS) GI50(MMS+PARPi)). Introduction of a...

Case Study 2 Pre Clinical Development of CDD0102A for the Treatment of Alzheimers Disease William S Messer PhD

Summary Muscarinic agonists have the potential to treat memory and cognitive deficits associated with Alzheimer's disease, and the potential to slow or stop the disease process. CDD-0102A, a small molecule, was discovered at The University of Toledo, and was characterized as a selective muscarinic agonist. It displayed promising biochemical activity, functional selectivity, in vivo efficacy, and was well tolerated at doses that improve memory function in animal models. NIH-RAID contributed to...

PI3K8selective inhibitors

Most 8-selective PI3K inhibitors are derived from IC87114 26, which has an IC50 of 130 nM against PI3K8 and > 100-fold selectivity over the a, p, and g isoforms 99,100 , and showed oral efficacy in a neutrophil-driven model of inflammatory arthritis 101 . Comparing crystal structures of d-selective versus pan-PI3K inhibitors has revealed a selectivity pocket that is occupied by the o-toluyl ring of 26 and related analogs 102 . Selective PI3K8 inhibitors can adopt a twisted propeller...

Nmda Receptor Hypofunction

The D2 antagonist activity of current antipsychotics led to the dopamine hypothesis, which states that the pathophysiology of schizophrenia is due to excessive dopaminergic neurotransmission and dysfunctional D2 signaling 6 . This hypothesis has prevailed for nearly 60 years however, it falls short as a complete explanation due to the deficiencies current antipsychotics exhibit against negative and cognitive symptoms. A growing body of evidence is emerging that suggests glutamatergic...

National Institute On Drug Abuse Medications Development Program

Purpose The Division of Pharmacotherapies and Medical Consequences of Drug Abuse (DPMCDA) includes a Medications Development Program (MDP). The Medications Discovery and Toxicology Branch (MDTB), the Chemistry and Pharmaceutics Branch (CPB) within the Medication Program support a pre-clinical translational therapeutics program. Their mission is to develop medications for the treatment of drug abuse, and to facilitate the translation of basic research findings into pharmacotherapies. The program...

Nonsarcosinebased inhibitors

Efforts in the area of second-generation nonsarcosine GlyT-1 inhibitors enjoy a stunning breadth of structural diversity. The field encompasses a highly competitive landscape and many of the scaffolds have been disclosed only in patent literature. Several patent applications claiming a class of inhibitors derived from the DA transporter (DAT) inhibitor methylphenidate (12) have been published 48-50 . A variety of structural modifications represented by analogs 13-15 have been claimed and...

Clinical Trial Status And Future Prospects

To date, three pharmaceutical companies have entered clinical trials with PHD inhibitors for the treatment of anemia with the most advanced being FG-2216. In clinical studies, compound 2 (likely FG-2216) showed a dose- and time-dependent elevation of plasma erythropoietin after oral administration 66 . Healthy volunteers were orally administered various doses of compound 2 and serum erythropoietin (EPO) concentrations were measured at various times. Compound 2 increased serum EPO levels in a...

Combination therapy with DNAdamaging agents

The intravenous PARPi PF-1367338 has been investigated in the clinic for several years, and recently a Phase II study coupling PF-1367338 with cisplatin was initiated in TNBC patients 46 . A Phase II study with combination therapy of PF-1367338 and TMZ in metastatic malignant melanoma patients has been reported 47 . In this melanoma clinical trial, there was an increase in both the partial response rate and disease stabilization compared to the use of TMZ monotherapy alone. This improved...

TRPA1 antagonists

In recent years there has been considerable effort directed at identifying potent selective antagonists for TRPA1 17 . Studies of TRPA1 knockout (KO) mice have revealed the importance of TRPA1 in pain signaling to chemical and mechanical stimuli as well as in mediating inflammatory pain 8,17-19 . The xanthine HC-030031 (22) has been extensively profiled by several research groups 17,20-23 . HC-030031 (22) blocks AITC (5) and CA (1) induced Ca2+ increases in TRPA1-expressing cells with IC50...

Aliphatic benzhydryl derivatives

The benzhydryl substituent is common to many reported N-type calcium channel blockers. A recently reported series derived from the neuroepi-leptic flunarizine (5), which exhibits N-type calcium channel potency in a whole-cell patch-clamp assay (IC50 0.08 jmM) as well as L-type potency (IC50 0.31 j M) 64 , in addition to the T-type activity noted above (IC50 0.53 jmM vs. Cav3.1) 52 . A successful optimization effort based on 5 was recently reported to improve the subtype selectivity of this...

Oxoglutarate analogs

The majority of small-molecule PHD inhibitors in both the recent patent and peer-reviewed literature are structural analogs of 2-OG, many designed with the aid of computational docking techniques employing literature or novel x-ray cocrystal structures. The structure of 2-OG bound to certain dioxygenases is known 15 and more recently, that of 2-OG bound to PHD2 has been solved 32 . Nearly all chemotypes published take advantage of a carboxylate salt bridge interaction with Arg383 in the active...

Role of opioid receptors in GI motility

There is a plethora of in vitro and in vivo pharmacological data with MOR-selective agonist and antagonists implicating MOR in the disruption of GI function by opioid analgesics 2,9 . This pharmacology is consistent with studies demonstrating the expression of MOR mRNA protein in distinct enteric neurons and intestinal muscle cells in rodents, pigs, and humans 9 . The pharmacological data supporting the essential role of MOR in the inhibition of GI transit by opioids was confirmed genetically...

Pfizer Inc v Apotex Inc amlodipine besylate

Case History In an attempt to protect Norvasc from generic competition, Pfizer sued Apotex in district court, asserting that Apotex infringed upon Claims 1-3 of U.S. Patent No. 4,879,303 '303 . Pfizer won at the district court level, but lost on appeal at the Federal Circuit Analysis This case, in many ways, is the antithesis of Sanofi-Synthelabo v. Apotex, Inc., presented in Section 5 above. Pfizer sued Apotex to prevent Apotex from selling generic Norvasc amlodipine besylate , asserting that...

Takeda Chem Indus Ltd v Alphapharm Pty Ltd pioglitazone

Case History Takeda, in an attempt to protect Actos from generic competition, sued various generic pharmaceutical manufacturers collectively Alphapharm for infringing the claims of U.S. Patent No. 4,687,777 '777 . At trial, Alphapharm asserted that the compounds covered by the claims of the '777 patent were obvious in view of a prior art compound. The district court found the compounds covered by the claims of the '777 patent nonobvious and held the '777 patent valid. On appeal, the Federal...

Activitybased detection of enzymes

Activity-based protein profiling ABPP is a chemical proteomic strategy in which active-site-directed covalent probes are used to profile the functional states of enzymes in complex proteomes. Activity-based probes ABPs can distinguish active enzymes from their inactive zymo-gens or inhibitor-bound forms. They contain a reactive group intended to modify enzyme active sites covalently and a reporter group typically rhodamine or biotin that assists in detection and identification of protein...

Preclinical And Clinical Applications

This section contains examples applying the presented concepts in which measured Cb andfu b, satellite rat neuropharmacokinetic studies, and or measured Cp and fu,p were used to determine compound-dependent Cb u required for a specific mechanism-mediated in vivo effect. The presented studies demonstrate the utility of Cb,u in defining target pharmacology relationships for small molecules affecting transmembrane proteins.

Structure Of Phd Enzymes And Catalytic Mechanism

The catalytic mechanism of 2-OG-dependent dioxygenases has been thoroughly reviewed elsewhere 15,16 . While full-length PHD enzymes have yet to succumb to crystallization efforts, the x-ray structures of two catalytically active, truncated PHD2 enzymes PHD2181_426 and PHD2181_417 in complex with Fe II and isoquinoline inhibitor and 2-OG mimetic 1 were reported in 2006 17 . An additional PHD2 cocry-stal structure with isoquinoline inhibitor 2 was deposited in the RCSB protein data bank in 2006...

Other physicochemical roadblocks

Recently, there have been many studies associated with the negative impact of designing chemical matter outside of drug-like space. What constitutes drug-like space hinges on a number of parameters with the majority related to a broad spectrum of physicochemical properties. Indeed, many studies not satisfied with well-established physicochemical parameters have had cause to conceptualize and calculate others such as Ligand efficiency LigE 91 , ligand Lipophilicity efficiency LLE 6 , aromatic...

TRPV2 modulators

Modulation of the TRPV2 channel is species specific. TRPV2 is activated by heat gt 52 C and 2-aminoethoxydiphenyl borate 2-APB 41 in both rat and mouse however, human TRPV2 does not respond to either heat or 2-APB 41 . Recently, cannabinoids such as cannabindiol 42 and 8-9-tetrahydrocannabinol 43, THC have been disclosed as agonists for rat TRPV2 with EC50 values of 3.7 and 15.5 jmM, respectively 42,43 . Probenecid 44 is also an agonist of rat TRPV2 EC50 31.5 jmM 44,45 . Ruthenium Red and...

Alvimopan Entereg

Alvimopan 3 is a potent, orally active PAMOR antagonist with a sub-nanomolar affinity at MOR and approximately 10-fold selectivity versus DOR and KOR 26 . When tested at 1 or 10 jmM, 3 had no significant activity in a broad range of nonopioid receptors, ion channels, and enzymes 9 . Relative to full agonists, 3 has no positive intrinsic activity at human MOR and DOR, and guinea pig KOR 26 . In a mouse hot-plate study, subcutaneous dosing of 3 inhibited morphine-induced antinoci-ception ID50 6.0...

Ligand Lipophilicity Efficiency

Given the role of lipophilicity in influencing drug potency, pharmacokinetics, and toxicity reviewed above, it was proposed that chemists should target increased ligand lipophilicity efficiency, LLE, as an important objective for lead generation and optimization programs 6 . LLE, or Lipophilic ligand efficiency, LipE 10 , was defined as in Equation 1 below and is the ratio of compound potency to lipophilicity or, put another way, the quantity of potency per unit of lipophilicity. Note that both...

Pyrazole tetrazoles

The replacement of the acid in the pyrazole analog 43 with a tetrazole bioisostere yielded analog 46, a partial agonist in the cAMP assay 101 . Compound 46 effectively reduced plasma FFA in mice, but did not induce vasodilation at the maximum feasible dose 400 mg kg . Unlike niacin, 46 did not activate ERK 1 2 mitogen-activated protein kinase MAPK pathways in vitro. Furthermore, preadministration of 46 in mice blocked niacin-induced, but not PGD2-induced vasodilation. Taken together, these...

FabI Inhibitors

Enoyl-ACP reductase ENR uses the cofactor NAD P H to reduce the double bond in the trans-2-enoyl-ACP to the corresponding acyl-ACP product in the ultimate and rate-limiting step of the elongation cycle 38 . The FabI isoform is an essential target in pathogens such as E. coli, S. aureus, Acinetobacter baumannii, Bacillus anthracis, H. pylori, Klebsiella pneumoniae, Neisseria meningitidis, Salmonella typhi, and M. tuberculosis also called InhA for the latter . Clinical success mentioned in the...

Imidazopyridines and thiazolylpyrimidines

Imidazopyrazines, such as 24, are one of the few Syk inhibitor chemo-types lacking an embedded meta-diamino scaffold 93 . Instead, a phenyl ring at the 6-position and an aniline at the 8-position have been claimed. Preferred compounds have IC50's lt 10 nM against Syk and inhibit B-cell proliferation with EC50's lt 1 M. As a measure of functional selectivity, the compounds are claimed to be at least fivefold more potent in inhibiting proliferation of B-cells versus T cells. The X-ray crystal...

Case Study Development of Istodax romidepsin NSC 630176 depsipeptide Fujisawa Pharmaceutical Co

Summary Romidepsin is a novel natural product histone deacetylase HDAC inhibitor that was developed in collaboration with Fujisawa Pharmaceuticals now Astellas Pharma . Fujisawa originally submitted romidepsin as NSC 630176 in 1990 for NCI60 anti-proliferative activity evaluation 8 . Based partly on its unique, bicyclic peptide structure, and pattern of activity in the NCI60, the DTP within NCI subsequently performed animal PK and efficacy evaluation, as well as in vitro and in vivo safety...

Mouhmed Balchnat

Mutat, 1994, 4, 167. 2 The website http www.cff.org is maintained and updated by the Cystic Fibrosis Foundation. It provides a wealth of data on all aspects of the disease, the patients, science, treatment, and the therapeutic pipeline. 3 M. R. Knowles, M. J. Stutts, A. Spock, N. Fischer, J. T. Gatzy, and R. C. Boucher, Science, 1983, 221, 1067. 4 P. M. Quinton, Nature, 1983, 301, 421. 5 J. R. Riordan, J. M. Rommens, B. Kerem, N. Alon, R. Rozmahel, Z. Grzelczak, J....

Sarcosinebased GlyT1 inhibitors

The design of many first-generation GlyT-1 inhibitors started with sarcosine and appended large N-linked hydrophobic moieties to it. In many cases, motifs were chosen to exploit the homology that GlyT-1 shares with other members of the SLC6 family. Thus, numerous early sarcosine-based inhibitors contain structural features shared with inhibitors of related transporters. The first sarcosine-based inhibitor, NFPS or ALX-5407, 3 , bears close resemblance to the selective serotonin reuptake...

Triclosan and analogs

In addition to its broad-spectrum biocidal activity, triclosan 22 displays reversible inhibition of E. coli FabI with a picomolar Ki for binding the enzyme-cofactor complex 4 . Triclosan entry results in the reordering of a loop of amino acids close to the active site, making it a slow, tight-binding inhibitor 41 . NB2001 23 , a prodrug of triclosan, has been developed based on the enzyme-catalyzed therapeutic activation ECTA concept. Evidence supporting ring opening of the cephalosporin moiety...

TRPV4 modulators

TRPV4 was identified a decade ago as an osmotransducer that is expressed in lung, heart, kidney, airway muscle cells, sensory neurons, brain, skin, gut, sympathetic nerves, inner ear, endothelium, and fat tissue 58-61 , TRPV4 is activated by heat 27-34 C , endogenous substances such as anandamide 59, AA and the arachi-donic acid metabolite 5,6-epoxyeicosatrienoic acid 60, 5,6-EET , a plant dimeric diterpenoid bisandrographolide A 61, BAA , and the semisynthetic phorbol ester...

Barbituric acid derivatives

Fusion of a barbituric acid motif and a pyrone ring afforded compounds containing a novel pyranopyrimidine core L that were discovered as GPR109A agonists 92,93 . This core appears to be distinct from other fused bicyclic cores such as xanthine and anthranilide based on their poor overlap. Furthermore, several compounds, exemplified by 39 and 40, provided remarkable potency in the cAMP assay. The critical acidic functional group is present as the N-H of barbituric acid motif which has a...

TRPV3 modulators

TRPV3 is found in pain-signaling neural pathways such as DRG, TG, and spinal cord, as well as in keratinocytes, brain, skin, and tongue 47 . TRPV3 is activated by warm temperatures gt 32 C and 2-APB 41 as well as by natural products such as camphor 46 , thymol 20 , carvacrol 47 , eugenol 48 , vanillin 49 , menthol 50 , and synthetic ethyl vanillin 51 48-50 . Incensole acetate 52, IA , a plant-derived diterpenoid, is reported to increase Ca2 influx in HEK293 cells stably expressing mouse TRPV3...

TRPV1 antagonists

TRPV1 is a nonselective cation channel predominantly expressed in sensory neurons and activated by capsaicin, heat gt 42 C , pH lt 5.4 , and noxious stimuli. Several compounds have advanced into clinical development and have been extensively covered in recent reviews 5,34-39 . Among these, MK-2295 structure not disclosed , AMG 517 38 , SB-705498 39 , and GRC-6211 structure not disclosed have reportedly encountered safety issues 35 . In phase II clinical trials with MK-2295, patients experienced...

In Vitro Assays And In Vivo Animal Models

Five major in vitro assays have been employed to evaluate GPR109A agonists a 3H-niacin-binding displacement assay and a guanine nucleotide exchange functional assay on the GPR109A-expressing CHO cell membranes 25 , a calcium mobilization assay 37 , a forskolin-stimulated cyclic adenosine monophosphate cAMP accumulation assay in CHO-hGPR109A cells 27 , and a lipolysis inhibition assay in human adipocytes 29 . To evaluate the in vivo therapeutic index TI of GPR109A agonists regarding FFA...

Recent Clinical Data

Three orally administered investigational CFTR modulators are currently being evaluated in clinical studies VX-770 7 , VX-809 structure not currently disclosed , and Atularen 16 64,65 . Compound 16 is being evaluated in a longer-term, multicenter, randomized, double-blind, placebo-controlled Phase III study in patients with nonsense CFTR mutations. In a Phase Ila trial of this investigational drug in pediatric and adult CF patients, it was shown that oral administration of Atularen was well...

Conclusions

Since the discovery of GPR109A, the high-affinity niacin receptor, multiple classes of GPR109A agonists have been discovered and developed, of which many seem to possess excellent potency in FFA suppression and good pharmacological properties with regard to reduced vasodilation. This chapter highlighted eleven structural classes of orthosteric GPR109A agonists and one class of allosteric agonists. All series of orthosteric agonists invariably have an acidic proton which likely interacts with...

TRPA1 agonists

Aitc Trpa1

TRPA1, also known as ANKTM1, is expressed in the polymodal C- and A-5 fiber sensory neurons of the dorsal root ganglia DRG and trigeminal ganglia TG . It is coexpressed with TRPV1 in a subset of TRPVl-contain-ing neurons. Recombinant TRPA1 is activated by noxious cold lt 17 C and a variety of natural compounds that are nocifensive or produce burning sensations 6,7 . Several exogenous electrophiles such as cinna-maldehyde 1, CA, EC50 19 jmM , oxindole 2, SC, EC50 0.8 jmM , oxi-ndole alkyne 3,...

Roles of Btk Syk and PI3K in Bcell biology

Btk Pi3k Syk Fcr Signaling

Btk, Syk, and PI3K are expressed in B-cells as well as other cell types which may play a role in disease, including monocytes, macrophages, and mast cells. Given the validation of biologic therapies targeting B-cells, this chapter will focus on advances in targeting these kinases to modulate B-cell activity. Btk, Syk, and PI3K are cytoplasmic kinases that sit at the apex of the B-cell signaling cascade and are in position to profoundly impact downstream signaling events and consequent B-cell...

Diacylglyceride Oacyltransferases

DGATs 35 along with acyl-CoA monoacylglycerol acyltrasferase type 3 MGAT3 36 are the enzymes responsible for the completion of TG synthesis from an acyl-CoA and a diacylglyceride. Two isoforms of human DGAT are known. DGAT1 is located mainly in enterocytes in the small intestine and is primarily responsible for recombining dietary TGs upon absorption and for their incorporation into nascent chylomicrons for excretion 37,38 . DGAT2 is expressed primarily in liver, adipose tissue, and, to a...

References

Snutch in Encyclopedia of Neuroscience, ed. R. S. Larry , Academic Press, Oxford, 2009, p. 427. 2 W. A. Catterall, E. Perez-Reyes, T. P. Snutch, and J. Striessnig, Pharmacol. Rev., 2005, 57,411. 3 C. J. Doering and G. W. Zamponi, Curr. Pharm. Des., 2005, 11, 1887. 4 W. A. Catterall in Encyclopedia of Neuroscience, ed. R. S. Larry , Academic Press, Oxford, 2009, p. 543. 5 A. A. Kochegarov, Cell Calcium, 2003, 33, 145. 6 M. Spedding and P. M. Vanhoutte, J. Cardiovasc. Pharmacol., 1993,...

StearoylcoA Desaturases

SCDs are a family of microsomal Fe-based metalloenzymes. They act on long-chain saturated acyl CoAs and introduce a cis-double bond at the C-9 or C-10 position. For example, SCDs convert stearic acid into oleic acid, and palmitic acid into palmitoleic acid. Monounsaturated FAs constitute a major component of TGs, cholesteryl esters, and phospholipids. The reaction requires molecular O2 and NADH and generates H2O in the process 3,4 . Two isoforms SCD1 and SCD5, also known as SCD2 in rodents have...

Irreversible inhibitors

Bmx Inhibitors

PCI-32765 1 is the only Btk inhibitor which has been reported to have advanced to clinical trials 40 . Modeling of pyrazolopyrimidine 2 suggested that replacement of the cyclopentyl moiety could position an electrophilic group in proximity to Cys481, and subsequent optimization led to 1 41 . Compound 1 inhibits Btk with an IC50 of 0.8 nM, and covalent binding to Btk was confirmed by mass spectrometry and washout experiments. In the Ramos B-cell line, 1 inhibits BCR-induced calcium flux IC50 40...

Microsomal Triglyceride Transfer Protein

MTP is responsible for the transfer of TGs and cholesteryl esters from the endoplasmic reticulum ER to lipoprotein particles VLDL in hepatocytes in the liver and chylomicrons in endocytes in the intestine for secretion 52 . It is a heterodimer consisting of a unique large subunit essential for lipid transfer encoded by the mttp gene and a smaller subunit, the ubiquitous ER enzyme protein disulfide isomerase 53 . Abetalipoproteinemia or Bassen-Kornzweig syndrome, a potentially disabling,...

Quinazolines and quinazolinones

A series of 2-amino-3,4-dihydro quinazolines have been extensively explored as selective T-type calcium channel antagonists. A recent disclosure included KYS05090 9 with an IC50 of 41 nM on the Cav3.1 subtype of the T-type channel and 120-fold selectivity versus the N-type calcium channel Cav2.2 55 . A pharmacophore model was recently published based on this and related structures 56 , but no other selectivity or in vivo activity have been disclosed since the original report. A series of...