the cutting edge of chemistry, jan. - mar. 2010 -- pharma matters report

NEW!Action-packed chemistry review providing insight into the latest synthesis schemes, scaffolds, mechanisms of actions and new structures advancing drug discovery and development.

THE CUTTING EDGE OF CHEMISTRYA PHARMA MATTERS REPORT.JANUARY - MARCH 2010

Image CopyrIght: REUTERS/Bogdan Cristel

http://www.thomsonreuters.com

A PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY

The Cutting Edge of Chemistry discloses new ideas and achievements in the biomedical research field with the chemist’s perspective in mind and is a recently launched new addition to the Pharma Matters report series. The report has been organized into sections that delineate essential aspects of the search for better and safer drugs.

The Organic Synthesis Scheme Showcase presents a selection of cutting-edge organic syntheses for drugs currently on the market or in development worldwide and described in premier publications in medicinal chemistry as well as in the current patent literature. This section provides access to the state-of-the-art synthetic methods for bioactive compounds, as well as demonstrating how new synthetic methods lead to interesting intermediates or drugs.

Chemists often start with a novel chemical structure in the drug discovery process. Molecular scaffolds are the building blocks with which they build more sophisticated active compounds. Chemists have so far explored only small regions of the vast molecular universe looking for therapeutic agents, but are constantly pushing back the frontiers. Scaffolds on the Move relates efforts in this arena.

Finding new targets to address more selectively is crucial to sustaining a competitive advantage in pharmaceutical research. Indeed, accurate target identification and validation processes in the very early stages of any drug R&D project can make the difference between success and failure in the clinical application of a new drug as well as a strong intellectual property strategy. The New Molecular Mechanisms of Action feature highlights this critical aspect of early-stage research.

The Starting Line includes a series of new molecular entities just entering the R&D pipeline. Novel, biologically active molecules picked from the current scientific literature and meetings are revealed in this section. Not surprisingly, these research projects from industry and academia are the culmination of the earlier steps in the process: discovery of an original chemical structure, identification of an appealing new mechanism of action, and determination of synthetic feasibility.

Thomson Reuters has widely applied in the design of its products and services the dynamics driving end-user information needs. The Cutting Edge of Chemistry is the most recent addition to this concept and we expect it will constitute, together with the existing Pharma Matters reports, a useful addition to your reading list.

IN THIS ISSUE1 orgaNIC SyNtheSIS SCheme ShoWCaSe

Marine natural products prove useful as leads repeatedly. A novel synthetic approach to a rare peptide from a marine sponge opens the door for evaluating its promising biological activity.

4 SCaFFoLDS oN the moVeA wide range of new skeletons emphasize the point that novel chemical scaffolds with biological activity underpin major advances in medicinal chemistry.

7 NeW moLeCULar meChaNISmS oF aCtIoNMechanisms are key to finding ways to improve a given drug design and also to find still more potent leads with fewer potential side effects.

9 the StartINg LINe & target FoCUSHighlighted in this issue, the rise of new molecular entities in the cancer and CNS R&D arenas.

PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 1

ORGANIC SYNTHESIS SCHEME SHOWCASE: SoakINg up polyTheoNaMIDe B SyNTheSISpolytheonamides a and B (pa and pB) were first isolated from the coral reef sponge Theonella swinhoei, a well-known source of novel natural products with physiological activity. What makes pB particularly interesting is that it can stimulate an ion flux across cell membranes and quickly kill cells. The compound has been investigated for a potential role in treating leukemia as it is cytotoxic against a strain of mouse leukemia p388 cells.

Researchers have assumed that a symbiotic microorganism present in T. swinhoei is responsible for the biosynthesis of pB. as such, the total synthesis of pB has represented a challenge. Masayuki Inoue of the graduate School of pharmaceutical Sciences, The university of Tokyo, and colleagues have now obtained good yields in a laboratory synthesis involving a coupling reaction between appropriate segments of pB using thioligation with silver ions [1].

In detail, the team uses a four-stage synthesis. The first step is the synthesis of the required amino acids, which are not commonly found in proteins. The second stage is the preparation of the required peptide fragments by solid-phase assembly of the protected amino acids over a Wang resin. after derivatization of the three fragments into thioesters, they are inter-connected, in the third stage, by means of silver ions in processes with yields of about 85%. The fourth and final step involves global deprotection.

The researchers add that the stereoselective synthesis of the sulfoxide from the sulfide precursor and its stereochemical assignment were not simple tasks, primarily because chiral reagents for sulfide oxidation do not exhibit diastereoselectivity. however, by turning to katsuki conditions the team was able to promote a highly diastereoselective oxidation to the final product.

This invaluable approach to peptide disconnections and protecting-group strategy not only has made it much more straightforward to synthesize such a significant compound as pB, but could allow chemists to construct other polypeptide drugs for testing against a range of disorders. Inoue and colleagues also point out, “The synthetic material now available will allow studies of the relationships between its conformational properties, channel functions and cytotoxicity.”

Indeed, Inoue and colleagues conclude, “This attempt to gain precise atom-by-atom control of the structure will provide the first chemical basis for systematically correlating its molecular structure and biological function.”

INTEGRITY ENTRY NUMBER: 691631

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2 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY

Synthesis scheme for Polytheonamide B (Part 1)

NH

O

CH3 C H3OH

NH

O

O

NH

NH

O

O

NH

C H3OH C H3

Ile NH

O

FmocNH

O

S

O

EtO L T le

NH

O

CH3 C H3OH

NH

O

O

NH

NH

O

O

NH

C H3OH C H3

Ile NH

O

FmocNH

O

ON

NN

O

L T le

NH

C H3CH3

O

NH

O

NH

O

Trt

CH3C H3

NH S+ C H3

O

OH

O

NH

NH

O

O

Trt

NH

O

O

NH

NH

O

O

NH

C H3C H3

NH

O

O

NH

NH2

O

O

NH

C H3

ValAlaVal D Ser

t BuOC H3

Ile

D Thr(tBu)Thr(tBu) G ln(Trt)

NH

C H3CH3

O

NH

O

NHO

Trt

CH3C H3

NH S+ C H3

O

O

NH

NH

O

O

Trt

NH

O

O

NH

NH

O

O

NH

C H3C H3

NH

O

O

NH

NH

O

O

NH

C H3

NH

O

CH3 C H3OH

NH

O

O

NH

NH

O

O

NH

C H3OH C H3

ValAlaVal

Ile G ly Ile

D Ser

t BuOC H3

G ly NH2L T le

OH D Thr(tBu) G ln(Trt)Thr(tBu)

NH2

O

C H3CH3

C H3

OH

HOOBt, AgNO 3, DIEA

continues

(I)

(II)

Pip

(III)

(IV)L Tle


S

O

OEtNH

O

C H3CH3 OH

NH

O

CH3

HNH

O

O

NH

C H3

NH

O

CH3 C H3

OH

NH

O

O

NHC H3

NH2O

G ly Ala G ly

Ala NH

O

C H3

Fmoc

L T le

D T le

Ala G ly

NH

C H3CH3

O

NH

O

NHO

Trt

CH3C H3

NH S+ C H3

O

O

NH

NH

O

O

Trt

NH

O

O

NH

NH

O

O

NH

C H3C H3

NH

O

O

NH

NH

O

O

NH

C H3

NH

O

CH3 C H3OH

NH

O

O

NH

NH

O

O

NH

C H3OH C H3

ValAlaVal

Ile G ly Ile

D Ser

t BuOC H3

G ly NH2L T le



NH

C H3CH3

O

NH

O

NHO

Trt

CH3C H3

NH S+ C H3

O

O

NH

NH

O

O

Trt

NH

O

O

NH

NH

O

O

NH

C H3C H3

NH

O

O

NH

NH

O

O

NH

C H3

NH

O

CH3 C H3OH

NH

O

O

NH

NH

O

O

NH

NH

O

C H3CH3 OH

NH

O

CH3

HNH

O

O

NH

C H3

NH

O

CH3 C H3

OH

NH

O

O

NHC H3

NH2O

C H3OH C H3

ValAlaVal

Ile G ly Ile

Ala

G ly

G ly Ala G ly

Ala

D Ser

t BuOC H3

G ly

Ala NH2D T le

L T le

L T le

NH2

O

C H3CH3

C H3

OH continues

continued

1) HOOBt, AgNO3, DIEA

2) Pip

(IV)

(V)

(VI)D Tle



NH

O

CH3 S+

CH3

O

C H3

NH

O

O

NH

NH

O

OH

O

NH

C H3 C H3

NH

O

O

NH

NH

O

O

NH

C H3

NH

O

CH3 C H3OH

NH

O

O

NH

NH

O

O

NH

NH

O

C H3CH3 OH

NH

O

CH3

HNH

O

O

NH

C H3

NH

O

CH3 C H3

OH

NH

O

O

NHC H3

NH

O

C H3

C H3

C H3

CH3

O

O

C H3CH3

NH2O

C H3OH

C H3

C H3

D AsnG lnD Thr

Val D AsnAlaVal

Ile G ly Ile

Ala

G ly

G ly

G ly Ala

Ala AlaAla

D AlaG ly

G ly

ValD Ser

L T le D T le L T le

L T le

D T leD T le

L T leG ly

L T le

G ly

ThrC OOH

NH

O

C H3

C H3

C H3

CH3

O

O

C H3CH3 G ly

S

D AlaL T leD T leL T le

L T le

D T leAla

O

EtO G ly

G ly


NH

C H3CH3

O

NH

O

NHO

Trt

CH3C H3

NH S+ C H3

O

O

NH

NH

O

O

Trt

NH

O

O

NH

NH

O

O

NH

C H3C H3

NH

O

O

NH

NH

O

O

NH

C H3

NH

O

CH3 C H3OH

NH

O

O

NH

NH

O

O

NH

NH

O

C H3CH3 OH

NH

O

CH3

HNH

O

O

NH

C H3

NH

O

CH3 C H3

OH

NH

O

O

NHC H3

NH2O

C H3OH C H3

ValAlaVal

Ile G ly Ile

Ala

G ly

G ly Ala G ly

Ala

D Ser

t BuOC H3

G ly

Ala NH2D T le

L T le

L T le

continued

1) HOOBt, AgNO 3, DIEA

2) TFA

(VII)

(VI)

Diastereoselective oxidation of sulfide to sulfoxide (Katsuki conditions)

Fmoc

O

O

C H3

C H3

SCH3

NH

t-Bu Fmoc

O

OH

C H3

C H3

S+CH3

NH

O

1) H 2NCONH 2.H2O 2,di-µ-oxo Ti(salen)

2) TFA


SCAFFOLDS ON THE MOVENovel chemical scaffolds with biological activity underpin major advances in medicinal chemistry. In this issue, a wide range of new skeletons emphasize this point once again. For instance, a series of 2-arylbenzoxazoles from Merck & Co. offers hope in treating lipid disorders and atherosclerosis, while arthritis is the target of almirall’s new dihydroorotate dehydrogenase inhibitors. a promising skeleton, carene, from Novartis also features in this issue and offers a new lead for treating transplant rejection.

BENZOXAZOLE BLOCKS CHOLESTEROL TRANSFERMerck scientists have developed a series of 2-arylbenzoxazoles that block cholesteryl ester transfer protein (CeTp) and so might be useful in treating lipoprotein disorders and disorders of the coronary arteries as well as atherosclerosis. Their structure-activity studies on the impact of varying the substitution of the benzoxazole moiety suggest that substitution at the 5- and 7-positions is beneficial to CeTp inhibition. The most potent compound of the series has an IC50 of 28 nM.

THERAPEUTIC GROUP: Treatment of lipoprotein Disorders; Treatment of Coronary arteries and atherosclerosis Disorders

SOURCE: Smith, C.J.; ali, a.; Chen, l.; hammond, M.l.; et al.2-arylbenzoxazoles as CeTp inhibitors: Substitution of the benzoxazole moiety. Bioorg Med Chem Lett 2010, 20(1): 346.

STUDIED MECHANISM OF ACTION: Cholesteryl ester Transfer protein (CeTp) Inhibitors

ORGANIZATION: Merck & Co.


ANTI-INFLAMMATORY AMINO(ISO)NICOTINIC ACIDS arthritis is the focus of novel, patented dihydroorotate dehydrogenase (DhoDh) inhibitors from almirall, that are orally active and could be suitable for treating autoimmune conditions, such as rheumatoid arthritis. The potent amino(iso)nicotinic acid derivatives represent a new scaffold for DhoDh inhibitors, one biaryl derivative showing an IC50 of 6 nM against human DhoDh (featured molecule). Structure-activity studies and optimization of the series led to one particular compound (chemical structure undisclosed) with potent in vitro activity against human, rat and mouse DhoDh (IC50 values of 0.037, 0.034 and 0.07 µM, respectively) compared with that of teriflunomide (respective IC50 values of 1.5, 0.033 and 1.1 µM). The compound also inhibits proliferation of human peripheral blood mononuclear cells more effectively and has demonstrated efficacy in reducing inflammation, as measured by paw volume, in a rat model.

THERAPEUTIC GROUP: antiarthritic Drugs

SOURCE: erra, M.; Sanahuja, J.; Fonquerna, S.; Navarro, e.; et al.Best in class DhoDh inhibitors: evolution of clinical compounds.239th aCS Natl Meet (March 21-25, San Francisco) 2010, abst MeDI 461.

STUDIED MECHANISM OF ACTION: Dihydroorotate Dehydrogenase (DhoDh) Inhibitors

ORGANIZATION: almirall INTEGRITY ENTRY NUMBER: 691251

N

O

NH

O

O

C H3

OHC H3

C H3

NC

N

NH

O OHF

F

C H3

O F

FF


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IMIDAZO[1,2-a] PYRAZINE ANTICANCER DRUGSaurora-a (aRk1) kinase and aurora-B (aRk2) kinase are two enzymes over-expressed in tumors. Belonging to a family of three Ser/Thr kinases, they are critical regulators of mitosis, abundant in tumors, and so have been longstanding targets for anticancer compounds. Merck has recently disclosed novel dual inhibitors of aurora kinases a and B based on an imidazo[1,2-a] pyrazine scaffold. lead optimization allowed for the identification of progression candidates, albeit they showed poor oral bioavailability. The sites of metabolism were identified by studying the metabolic profile of a particular compound of the series.

THERAPEUTIC GROUP: oncolytic Drugs

SOURCE: kerekes, a.D.; esposite, S.J.; Doll, R.J.; yu, T.; et al.aurora kinase inhibitors based on the imidazolopyrazine core: Fluorine incorporation improves oral absorption and exposure.239th aCS Natl Meet (March 21-25, San Francisco) 2010, abst MeDI 146.

yu, T.; Tagat, J.R.; Zhang, y.; Xiao, y.; et al.Discovery of aurora kinase inhibitors based on 3,6,8-trisubstituted imidazo[1,2-a] pyrazine scaffold.239th aCS Nat Meet (March 21-25, San Francisco) 2010, abst MeDI 145.

STUDIED MECHANISM OF ACTION: aurora-a (aRk1) kinase Inhibitors; aurora-B (aRk2) kinase Inhibitors



PYRAZOLES AVOID REJECTIONemploying a high-throughput screening and hit-to-lead optimization approach, Novartis has come out with a new carene scaffold displaying selective S1p1 agonist properties. Furthermore, the key structural requisites for potent agonism were also outlined by building up a pharmacophore model for the S1p1 receptor, a biological target for immunosuppression and the treatment of transplant rejection.

THERAPEUTIC GROUP: Immunosuppressants; Treatment of Transplant Rejection

SOURCE: Zécri, F.J.; albert, R.; landrum, g.; hinterding, k.; et al.pyrazole derived from (+)-3-carene; a novel potent, selective scaffold for sphingosine-1-phosphate (S1p1) receptor agonists.Bioorg Med Chem Lett 2010, 20(1): 35.

Zécri, F.J.; albert, R.; Baenteli, R.; landrum, g.; et al.Discovery and optimization of multiple scaffolds of selective S1p1 receptor agonists.239th aCS Natl Meet (March 21-25, San Francisco) 2010, abst MeDI 31.

STUDIED MECHANISM OF ACTION: lysophospholipid edg1 (S1p1) Receptor agonists

ORGANIZATION: Novartis


C H3CH3

NS

N

N

N

NNH

CH3

NHN

C H3

OH

O

NN

CH3

CH3

C H3

NH




INHIBITING OSTEOARTHRITIS WITH (PYRIDIN-4-YL)-2H-TETRAZOLESThe treatment of osteoarthritis is a major target of modern drug discovery, and finding inhibitors of MMp-13 (collagenase 3) represents a promising approach. pfizer has now disclosed potent and highly selective MMp-13 inhibitors. The orally bioavailable compounds were built on a (pyridin-4-yl)-2H-tetrazole scaffold. By means of co-crystal structure analysis it was determined that the inhibitors bind at the S1’ active site pocket, while they are not ligands for the catalytic zinc atom. In a preclinical rat model of osteoarthritis one particular compound was shown to reduce levels of TIINe, a biomarker of cartilage degradation, hence suggesting an aptitude for cartilage protection.

THERAPEUTIC GROUP: Treatment of osteoarthritis

SOURCE: Schnute, M.e.; o’Brien, p.M.; Nahra, J.; Morris, M.; et al.Discovery of (pyridin-4-yl)-2h-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.Bioorg Med Chem Lett 2010, 20(2): 576.

STUDIED MECHANISM OF ACTION: MMp-13 (Collagenase 3) Inhibitors

ORGANIZATION: pfizer


FeatUreD SCaFFoLD

TUBULAR SCAFFOLDINGpolytheonamide B is the largest known nonribosomal peptide; it contains 48 amino acid residues. It is a linear polypeptide that forms an intriguing tubular structure, which allows it to generate membrane-spanning ion channels, which leads to its cytotoxic effects.

Quite unusually, it also comprises a sequence of alternating D- and l-amino acids interrupted only by a string of eight glycine residues and capped at the N-terminus by 5,5-dimethyl-2-oxohexanoate. It is this amino acid disposition that allows for a particular stabilization through hydrogen bonding.

The molecule is thereby twisted into its functional shape: a helicoidal channel where the residues stand pointing outwards.

THERAPEUTIC GROUP: oncolytic Drugs

MOST RECENT SOURCE: Inoue, M.; Shinohara, N.; Tanabe, S.; Takahashi, T.; et al.Total synthesis of the large non-ribosomal peptide polytheonamide B.Nat Chem 2010, 2: 280

ORGANIZATION: university of Tokyo


N

N

C H3

O

NH

N N

N

OH

O

OCH3

NH

O

CH3 S+

CH3

O

C H3

NH

O

O

NH

NH

O

OH

O

NH

C H3 C H3

NH

O

O

NH

NH

O

O

NH

C H3

NH

O

CH3 C H3OH

NH

O

O

NH

NH

O

O

NH

NH

O

C H3CH3 OH

NH

O

CH3

HNH

O

O

NH

C H3

NH

O

CH3 C H3

OH

NH

O

O

NHC H3

NH

O

C H3

C H3

C H3

CH3

O

O

C H3CH3

NH2O

C H3OH

C H3

C H3

D-AsnG lnD-Thr

Val D-AsnAlaVal

Ile G ly Ile

Ala

G ly

G ly

G ly Ala

Ala AlaAla

D-AlaG ly

G ly

ValD-Ser

L-T le D-T le L-T le

L-T le

D-T leD-T le

L-T leG ly

L-T le

G ly

ThrC OOH




NEW MOLECULAR MECHANISMS OF ACTION: MeThylaTIoN, ThaT’S The NaMe oF The gaMeThe mode of action of any product is key to understanding how to improve on any given design and how to find more potent leads with fewer potential side effects. In this issue, we highlight the mode of action of a wide range of compounds including several involved in cancer, photodamage, psoriasis and osteoarthritis, and even trypanosomiasis, complete with an example drug exhibiting the relevant Moa.

of particular interest are inhibitors of an important group of enzymes, DNa methyltransferases. These enzymes are important to the mechanism by which drugs in areas as disparate as cancer, malaria, and arthritis, work.

DNa methylation is an important step in gene expression in normal cells, and also in cancer cells. as such, the enzymes involved in the process are being keenly investigated for putative anticancer drugs.

among the DNa methyltransferases is DNMT1, a maintenance methylase. By contrast, DNMT3b serves as a de novo enzyme and has been shown to be involved in gene-specific methylation.

There are some 28 drugs developed by 35 companies or research organizations cited in Thomson Reuters Integrity relating to DNMT1 inhibition that are in various stages of research and development from biological testing to near launch. however, there is just one company, Methylgene, developing compounds that are specific to the related DNMT3b, in particular DNMT3b2 inhibition.

So, how are DNMT1 and DNMT3b related clinically and is there an advantage to ensuring both are considered in drug development?

Importantly, from a medicinal chemistry perspective, researchers have found that DNMT3b preferentially targets certain gene promoters in prostate cancer cells, pC3 cells, to be precise. The depletion of DNMT3b significantly reduces growth and migration of these cancer cells, offering a direct target for this form of cancer [2].

In the wider sense, however, the inactivation of tumor suppressor genes is central to the development of all common forms of human cancer. given that DNMT1 is the major factor in the methylation of genes, one might assume it would be the primary target. however, DNMT3b also plays a role [3]. experiments to investigate suppression of DNMT1 have been highly successful, but paradoxically human cancer cells that lack DNMT1 still retain a significant degree of genomic methylation, and so are potentially cancerous. Further


experiments that target DNMT1 and DNMT3b simultaneously, however, can almost completely eliminate methyltransferase activity and so potentially stifle cancerous growth [4].

The activity of DNMT1 and DNMT3b and their selective inhibition offers new opportunities for the development of anticancer drugs. Studies using post-translational modifications of the enzymes could provide new clues not only for biologists hoping to understand the behavior of these enzymes, but also for medicinal chemists hoping to find specific small molecules to inhibit the enzymes in the body in a controlled manner.

FormIN homoLogy 2 (Fh2) DomaIN INhIBItorS

epIDermaL retINoL DehyDrogeNaSe 2 (rDh-e2) INhIBItorS

pLaSma CeLL memBraNe gLyCoproteIN 1 (pC-1; Npp-1) INhIBItorS

DNa methyLtraNSFeraSe 3b2 (DNmt3b2) INhIBItorS

MAIN RELATED CONDITIONS: Cancer

MAIN RELATED CONDITIONS: Cancer; Photodamage; Psoriasis

MAIN RELATED CONDITIONS: Osteoarthritis


ORGANIZATION: University of Chicago

ORGANIZATION: York Pharma

ORGANIZATION: Pfizer

ORGANIZATION: MethylGene

DRUG NAME: SMIFH-2 DRUG NAME: YP-017





t. BrUCeI DoLIChoLphoSphate maNNoSe SyNthaSe (DpmS) INhIBItorS

eCtoNUCLeotIDe pyrophoSphataSe/phoSphoDIeSteraSe 2 (eNpp2; aUtotaXIN) INhIBItorS

LaCtate DehyDrogeNaSe a INhIBItorS

MAIN RELATED CONDITIONS: Trypanosomiasis (African sleeping sickness)



ORGANIZATION: University of East Anglia and University of St. Andrews

ORGANIZATION: Merck KGaA

ORGANIZATION: Johns Hopkins University

DRUG NAME: FX-11




NH

N

S O

O

BrO

SO O

N

NH

NH2

N

NOCH3

OCH3

N

S

NN

N N

NH

O

OHOH

OH

NH2

OCH3 C H3

O

OOOH

H

C H3

H

O

C H3

C H3

H

C H3

CH3 OH

O

NS

S

OO

OH

OH OH O

C H3

CH3

OH

OH

N

NH

NH

NH

OCH3

C H3NH2

O O

OH









THE STARTING LINE AND TARGET FOCUSThe Starting Line pinpoints new molecular entities (NMes) ready to progress into the R&D arena, providing information on pharmacological activity, originator and chemical structures of key compounds.

an increase in the number of NMes pertaining to CNS within the journal literature and at conferences was identified in the first quarter of 2010. a comparison of patents in Integrity from up to the end of 1999 with those from up to the end of 2009 ordered by therapeutic group also demonstrates an increase in CNS and cancer drug development.

INtegrIty pateNt treNDS

Number of Published Patents by Therapeutic Area SOURCE: Thomson Reuters Integrity

0 5000 10000 15000 20000

Immunomodulating

Renal-Urologic

Hematology

Dermatology

Gastrointestinal

Analgesic

Psychopharmacology

Musculoskeletal

Respiratory

Cardiovascular

Metabolic

Antiinfective

Endocrine

Neurology

Oncology

PRODUCT BY THERAPEUTIC GROUP

Up to end of 1999

From 2000 to end of 2009


a selection of the novel, biologically active molecules picked from the current scientific literature and meetings are revealed here.

SOURCE DETAILS ORGANIZATION: glaxoSmithkline

PRODUCT: gSk-1331268

CONDITION: Schizophrenia

MECHANISM OF ACTION: mgluR2 agonists


LITERATURE: D’alessandro, p.l.; Corti, C.; Roth, a.; ugolini, a.; et al.The identification of structurally novel, selective, orally bioavailable positive modulators of mgluR2.Bioorg Med Chem Lett 2010, 20(2): 759.

ORGANIZATION: deCoDe genetics

PRODUCT: D-159687

CONDITION: Cognitive disorders

MECHANISM OF ACTION: phosphodiesterase pDe4D Inhibitors


LITERATURE: Burgin, a.B.; Magnusson, o.T.; Singh, J.; Witte, p.; Staker, B.l.; Bjornsson, J.M.; Thorsteinsdottir, M.; hrafnsdottir, S.; hagen, T.; kiselyov, a.S.; Stewart, l.J.; gurney, M.e. Design of phosphodiesterase 4D (pDe4D) allosteric modulators for enhancing cognition with improved safety.Nat Biotechnol 2010, 28(1): 63.

ORGANIZATION: university of California, oakland

CONDITION: Fibrosis, cystic

MECHANISM OF ACTION: CFTR Channel activators; DeltaF508-CFTR Correctors


LITERATURE: Mills, a.D.; yoo, C.; Butler, J.D.; yang, B.; Verkman, a.S.; kurth, M.J.Design and synthesis of a hybrid potentiator - Corrector agonist of the cystic fibrosis mutant protein DeltaF508-CFTR.Bioorg Med Chem Lett 2010, 20(1): 87.

ORGANIZATION: Roche

PRODUCT: Ro-85

CONDITION: urinary incontinence; pain

MECHANISM OF ACTION: p2X3 Receptor antagonists


LITERATURE: Brotherton-pleiss, C.e.; Dillon, M.p.; Ford, a.p.; gever, J.R.; Carter, D.S.; gleason, S.k.; lin, C.J.; Moore, a.g.; Thompson, a.W.; Villa, M.; Zhai, y.Discovery and optimization of Ro-85, a novel drug-like, potent, and selective p2X3 receptor antagonist.Bioorg Med Chem Lett 2010, 20(3): 1031.

N

NN

N

C H3

N

N

Cl

OCH3

Cl

NH

NH2

O

SN

N

CH3

NH

N

O C H3 N C H3

O

N

SNH

ON

S

C H3

NH

O

Cl

OO

O

O

NHNH

O

N

C H3

O






SOURCE DETAILS ORGANIZATION: Intellikine, Merck Serono

PRODUCT: SW-30

CONDITION: arthritis, Cancer

MECHANISM OF ACTION: phosphatidylinositol 3-kinase delta (pI3kdelta) Inhibitors


LITERATURE: Williams, o.; houseman, B.T.; kunkel, e.J.; aizenstein, B.; hoffman, R.; knight, Z.a.; Shokat, k.M.Discovery of dual inhibitors of the immune cell pI3ks p110delta and p110gamma: a prototype for new anti-inflammatory drugs.Chem Biol (lond) 2010, 17(2): 123.

Berndt, a.; Miller, S.; Williams, o.; le, D.D.; et al.The p110delta structure: Mechanisms for selectivity and potency of new pI(3)k inhibitors.Nat Chem Biol 2010, 6(2): 117.


PRODUCT: Mk-6892

CONDITION: atherosclerosis, lipoprotein disorders

MECHANISM OF ACTION: Nicotinic acid (Niacin; gpR109a; hM74a) Receptor agonists


LITERATURE: Shen, h.C.; Ding, F.-X.; Raghavan, S.; Deng, Q.; et al. Discovery of a biaryl cyclohexene carboxylic acid (Mk-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate.J Med Chem 2010, 53(6): 2666.

ORGANIZATION: angioChem

PRODUCT: aNg-1007

CONDITION: Cancer, brain

MECHANISM OF ACTION: DNa-Intercalating Drugs


LITERATURE: Che, C.; yang, g.; Thiot, C.New angiopep-modified doxorubicin (aNg1007) and etoposide (aNg1009) chemotherapeutics with increased brain penetration.J Med Chem 2010, 53(7): 2814.

yang, g.; Che, C.; Thiot, C.; lacoste, M.-C.; et al.Development of new cytotoxic etoposide and doxorubicin derivatives using the epiC platform for increased brain penetration.239th aCS Natl Meet (March 21-25, San Francisco) 2010, abst MeDI 247.

Demeule, M.; Regina, a.; yang, g.; Che, C.; et al.New angiochem-modified doxorubicin with increased brain penetration and efficacy against brain tumors.Proc Am Assoc Cancer Res (aaCR) 2010, 51: 3578.

N

N NN

N

N

O

NH2

C H3

C H3

OH

CH3 C H3

N

N O

NH

O

N

OH

OHO

O

NH

O

O

O

O

O

O

OO

OH

OH

OH

NH2

OH

O

OH

CH3

C H3

CH3

HG lyTyr SerPhePhe G ly

O

O

NH

O

O

NH

O

O

O

O

O

O

O

O

O

O

O

O

O

O

OH

OH

OH

OH

OH

OH

NH2

NH2

NH

NH

OH

OH

O

O

CH3

CH3

C H3

CH3

ArgPhe Asn AsnG lu ArgG luTyr ThrC OOH G ly





SOURCE DETAILS ORGANIZATION: Merck & Co.; ligand

PRODUCT: SCh-1359113

CONDITION: Dementia, alzheimer’s type

MECHANISM OF ACTION: beta-Secretase 1 (BaCe1) Inhibitors


LITERATURE:Stamford, a.W.; Babu, S.; Caldwell, J.; Chen, X.; et al.Discovery of small molecule, orally active and brain penetrant BaCe1 inhibitors.239th aCS Natl Meet (March 21-25, San Francisco) 2010, abst MeDI 290.

Cumming, J.N.; Misiaszek, J.; Iserloh, u.; Mazzola, R.D.; et al.Novel iminopyrimidinone beta-Secretase inhibitors: part 1. p1-p3 SaR.239th aCS Natl Meet (March 21-25, San Francisco) 2010, abst MeDI 531.

ORGANIZATION: Novartis

PRODUCT: NIBR-785

CONDITION: Immunosuppression; Multiple sclerosis; Transplant rejection

MECHANISM OF ACTION: lysophospholipid edg1 (S1p1) Receptor agonists


LITERATURE:Zecri, F.J.; albert, R.; Baenteli, R.; landrum, g.; et al.Discovery and optimization of multiple scaffolds of selective S1p1 receptor agonist.239th aCS Natl Meet (March 21-25, San Francisco) 2010, abst MeDI 31.

ORGANIZATION: Johnson & Johnson

PRODUCT: JNJ-26273364

CONDITION: pancreatitis

MECHANISM OF ACTION: CCk1 (CCka) antagonists


LITERATURE:gomeza, l.; Wua, J.; Mania, N.S.; Basub, S.; Moravekb, J.; Breitenbuchera, J.g.Carboxylation reaction of a highly functionalized vinylic anion: a case of unexpected stability and reactivity.Tetrahedron Lett 2010, 51(7): 1110.

guy Breitenbucher, J.; McClure, k.; gomez, l.; Sehon, C.; et al.Value of Free-Wilson analysis in the discovery of CCk-1 receptor antagonists for the treatment of pancreatitis.239th aCS Natl Meet (March 21-25, San Francisco) 2010, abst MeDI 540.

S

NNNH

C H3

NH

OC H3CH3

CH3 C H3

O OOCH3

OCH3

NH

O NH2

NN

O

O

Cl

Cl

O OH

Cl





aLZheImer’S DemeNtIa target LaNDSCape

Integrity provides an interactive view of the targets and associated drugs in the CNS arena. In this issue, we offer a snapshot of the Targetscape for alzheimer ’s disease, the indication targeted by the Merck & Co. NMe featured on page 12 of this report. The target for this drug – BaCe1 – can be seen highlighted in red in this Targetscape.

SOURCE: Alzheimer’s Disease Targetscape, Thomson Reuters Integrity [May 2010]

aDDItIoNaL reFereNCeS:

[1] Inoue, M.; Shinohara, N.; Tanabe, S.; Takahashi, T.; et al. Total synthesis of the large non-ribosomal peptide polytheonamide B. Nat Chem 2010, 2: 280.

[2] yaqinuddin, a.; Qureshi, S.a.; Qazi, R.; abbas, F. Down-regulation of DNMT3b in pC3 cells effects locus-specific DNa methylation, and represses cellular growth and migration. Cancer Cell Int 2008, 8: 13.

[3] leu, y.W.; Rahmatpanah, F.; Shi, h.; Wei, S.h.; liu, J.C.; yan, p.S.; huang, T.h. Double RNa interference of DNMT3b and DNMT1 enhances DNa demethylation and gene reactivation. Cancer Res 2003, 63: 6110.

[4] Rhee, I.; Bachman, k.e.; park, B.h.; Jair, k.W.; yen, R.W.; Schuebel, k.e.; Cui, h.; Feinberg, a.p.; lengauer, C.; kinzler, k.W.; Baylin, S.B.; Vogelstein, B. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 2002, 416: 552.

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the cutting edge of chemistry, jan. - mar. 2010 -- pharma matters report

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