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GRAPHICAL ABSTRACTS

T DESIGN PROTEASE

OF

A NEW

SELECTIVE

INACTIVATOR

AND

CYSTE1NE ITS

Bioorg.

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MECHANISTIC

IMPLICATIONS

Amnon Albeck,* Rachel Persky and Sharon Klipcr Department of Chemisn'v Bar llan University, Ramat Gan 52900, Israel

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Cbz-Phe-epoxide was designed as a selective inactivator of cysteine proteases. It exhibits a time- and concentration-dependent inactivation of cysteine ? proteases, while showing no activity towards serine proteases. Initial studies / support an active-sile directed, mechanism-based mode of inactivation, s(I L ~ j ~

I THE DEVELOPMENT OF A NOVEL SERIES OF NON-PEP'rIDE TACHYI.~N1LN NKj RECEPTOR SELECTIVE ANTAGONISTS P. Boden, J. M. Eden, J. Hodgson, D. C. Horwell, M. C. Pritchard,* J. Raphy and N. Suman-Chauhan. Pm'ke-Davis Neuroscience Research Centre, A ddenbrookes Hospital Site, Hills Rd, CAMBRIDGE, CB2 2QB, UK.

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Bioorg. Med. Chem. Lett. 1995, 5, 1773 F

ph."~O, ' ~

NH(CH2)TNHCON}~. o

of non-peptide NK 3 receptor selective antagonists eg. 9b, have been prepared based upon a small molecule dipeptide-based lead structure Abstract : A novel series

(9b) NK3 , IC50= 73nM

I

CONSTRAINED ANALOGS OF KCVFM W I T H I M P R O V E D

('~sO2Hs/'~

Med. Chem. Lett. 1995, 5, 1767

[

Bioorg. Med. Chem. Lett. 1995, 5, 1779

i

INHIBITORY PROPERTIES AGAINST FARNESYL TRANSFERASE.

F-F Clerc . J-D. Gmtton , N. Fromage, Y. Leli6vre, M. Duchesne, B. Tocqu6, E. James-Surcouf, A. Commercton and J. Becquart, Rh6ne-Poulenc Rorer SA., CRVA, 13 Quai Jules Guesde, BP14, 94403 Vitry-sur-Seine (France) Constrained analogs of KCVFM have been synthesized. Replacement of Val-Phe with Val-Tic and (N-Me)Val-Tic led to dramatically more active analogs possessing favored extended conformations. Based on molecular modeling studies the design and synthesis of various conformational probes to be substituted for Val and Phe led to a rather good correlation between the ratio of extended conformers and inhibito~ properties.

A NEW ACHIRAL

REAGENT

FOR THE INCORPORATION

KC(N-MeWTicM~ , ~ o

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Bioorg. Med. Chem. Lett. 1995, 5, 1785

OF MULTIPLE AMINO GROUPS INTO OLIGONUCLEOTIDES

Carsten Behrens~, Kenneth H. Petersen, Michael Egholm, John Nielsen, Ole Buchardt and Otto Dahl Research Centerfor Medical Biotechnology, Department of Chemistry, University (~f Copenhagen, Universitetsparken 5, DK-2100. Copenhagen. Denmark. Abstract. The synthesis of a new functionalizedlinker reagent (1 0) for the incorporation of multiple amino groups into oligonucleotidesis described. The linker reagent is compatible with conventional DNA-synthesis,and can be incorporatedin good yields.

1761

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DMT~moO~

~Nipr2 10

I

Bioorg. Med. Chem. Lett. 1995, 5, 1791

A R T E M I S I N I N DERIVATIVES W I T H 12-ANILINE SUBSTITUTION: SYNTHESIS AND A N T I M A g A R I A L ACTIVITY

H-

Yong-Hua Yug',Ying Li", Yun-IAn Shib, Jnn-l)e Yank? and BeAn Wu b

ShanghaiInstitute ofMateria Medica,ChineseAcademyof Sciences, Shanghai200031,CHINA b Institute of Microbiology and Epidemiology, AcademyofMilitary Medical Sciences, Belting 100071 •

10 New artemisinin derivatives were synthesized by the reaction of dihydroartemisinin and aromatic amines in the presence of acidic catalyst. These compounds showed more effective in vivo against P. berghei in mice than artemisinin.

I

t4-ter

Bioorg. Med. Chem. Lett. 1995, 5, 1795

PUTATIVE ATYPICAL ANTIPSYCHOTICS WITH MIXED DOPAMINERGIC (DI, D2) AND SEROTONERGIC (5HT2) ACTIVITY: THE DESIGN EVOLUTION OF ZD3638 MT Klimas*, .IM Goldstein, DA Trainor, RT Jacobs, CJ Ohnmacht, RA Roberts, YK Yee, MO Terpko, SP Thomas, LA Cronk, CA Frank, GD Harris, J Hulsizer, JJ Lewis, FM McLaren, RC Mauger, GD Morosky, SM Ronkin, P Sienkewicz, RB Sparks, TG Ulatowski, R Wildonger

OH

Departmentof Medicinal Chemistry,Zeneca Pharmaceuticals,WilmingtonDE 19897

The pharmacological activity of a series of 9,10-dihydro-9, l 0-methanoanthracene methylene amines which function as mixed dopaminergic (DI/D2) and serotonergic (5HT2) antagonists is described. The work resulted in a putative atypical antipsychotic, ZD3638, of novel structure and pharmacological prof'de. I

I

1-NAPHTHYLMETHYLPHOSPHONIC ACID DERIVATIVES i AS OSTEOCLASTIC ACID PHOSPHATASE INHIBITORS Charles F. Schwender*, Scott A. Beers, Elizabeth Malloy, Keith Demarest Lisa Minor, K.H.W.Lau 1 The R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869 1 Department of Mineral Metabolism, Pettis Memorial V.A. Hospital, Loma Linda California 92357

ZD3638

Bioorg. Med. Chem. Lett. 1995, 5, 1801

7a R= Benzoyl

Inhibition of the enzyme, osteoclastic acid phosphatase (OAP) may be a viable approach to the treatment of osteoporosis. A series of arylmethylphosphonic acids were synthesized and shown to be inhibitors of OAP. The most potent inhibitor, bis-benzoyl-l-naphthytmethylphosphonic acid 7a had an IC50=1.4 uM

HYDROXYLATION AT C-Y OF DOXORUBICIN ALTERS THE SELECTED PHENOTYPE OF CELLULAR DRUG RESISTANCE Leonard Lothstein, Trevor W. Sweatman, Waldemar Priebe* Dept. of Pharmacology, University of Tennessee College of Medicine, Memphis, TN 38163 *Dept. of Clinical Investigations, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030

Hydroxylation at C-3' of doxorubicin (DOX) yields the uncharged congener hydroxyrubicin, which circumvents P-glycoprotein-mediated drug resistance without loss oftopoisomerase I1 inhibitoryactivity. Hydroxyrubicin-resistantcells exhibit a phenotype that is uniquely different from DOX resistance by expressing non-functionalP-glyeoproteinand hypersensitivityto anti-mitoticdrugs.

1762

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Bioorg. Med. Chem. Lett. 1995, 5, 1807 o

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on

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CCH2OH OH

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Bioorg. Med. Chem. Lett. 1995, 5, 1813 SYNTHESIS AND B I O L O G I C A L ACTIVITY OF ENANTIOMERS OF A C O N F O R M A T I O N A L L Y RESTRICTED CH~ 0 MUSCARONE ANALOG. Edwin S.C. Wu,* Robert A.Mack, Alex Kover, James T. Loch III, George MuUen, Robert J. Murray, Jack Gordon, +Anthony Machulskis,* Sally A. McCreedy +, James C. Blosser+ Department of Chemistry and Department of Biology, t Astra Arcus, P. O. Box 20890, Rochester, A~Y 14602, USA A short and efficient synthesis of both enantiomers of 2,8-dimethyl-l-oxa-8-azaspiro[4.5]-decan-3-one is described. The biological activity o f the racemate resides predominantly in the S-enantiomer. While the S-isomer is a full M2-agonist, the R-isomer is devoid of M2 efficacy.

Y I Bioorg. Med. Chem. Lett. 1995, 5, 1819

AROMATIC AMINO ACID PHOSPHORAMIDATE DI- AND TRIESTERS

OF 3 ' . A Z I D O - 3 ' - D E O X Y T H Y M I D I N E

L

CH~

t.

(AZT) ARE

NON-TOXIC INHIBITORS OF HIV-1 REPLICATION, Carston R. Wagner,*1 Edward J. McInte¢, 1Raymond F. Schinazi,§ and Timothy W. Abrahaml,f Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota

55455, ~Department of Pediatrics, Emory University School of Medicine, Veteran Affairs. Medical Center, Decatur, Georgia 30033 Abstract. PBMC treated with active non-toxic phenylalanine and tryptophan phosphoramidate diesters of AZT contained four fold more phosphorylated A z r than those treated with AZT, and no free AZT.

. MeO2C ~

% OR, N t P ~ O / AZT H

FUNGAL METABOLITE OF NAFTAZONE INHIBITS NITRITE PRODUCTION BY ACTIVATED MURINE MACROPHAGES

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[

k

Bioorg. Med. Chem. Lett. 1995, 5, 1825

j. OUAZZANI *, C. SERVY *, C. BLOY ¢ and C. DUCROCQ *

• lnstitutde Chimiedes SubstancesNaturelles,CNRS,91198 Gif-sur-Yvette,FRANCE ~"Laboratoires CASSENNE,17 ruede Pontoise,95520Osny,FRANCE Abstract.The fungusMucorplumbeus catalyzesthe enzymaticcyelizauonof naftazone I to naphtho-(l,2-e)-(1,2,4)triazine-(3H)-one2. This compoundinhibitsthe inductionand the expressionof NO-synthaseby activatedroutine peritonealmacrophages. O N,'AJ~NH

Naflazo~ l

Naphtho-(l.2-e)-(l.2.4htnazm~(3H~ 2

N-(1-PHENYL-2-BENZIMIDAZOLYL)-N'-PHENYLUREA DERIVATIVES AS POTENT INHIBITORS OF ACYLCOA.~HOLESTEROL ACYLTRANSFERASE (ACAT). Toshiaki K u m a z a w a , * Hiroyuki Harakawa, Hiromi Fukui, Shiro Shirakura, Eiko Ohishi, and Koji Yamada

I

Bioorg. Med. Chem. Lett. 1995, 5,

Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Nagaizumi, Shizuoka, 411 Japan. A novel series of N-(1-phenyl-2-benzimidazolyl)-N'-phenylurea derivatives were prepared as ACAT inhibitors. These compounds showed potent ACAT inhibitory activity in vitro (liver microsomes from cholesterol-fed rabbits) and hypocholesterolemie activity in vivo (cholesterol-fed golden hamsters).

1763

4-(2-PYRIDYL)-2,2-DIMETHYLNAPHTHALEN-1-ONES Bioorg. Med. Chem. Lett. 1995, 5, 1833 AS N E W P O T A S S I U M C H A N N E L A C T I V A T O R S WITH INCREASED AIRWAYS SELECTIVITY Carmen Almansa*, Luis A. G6mez, Femando L. Cavalcanti, Ricardo Rodrfguez, Julifin Garcfa-Rafanell, and Javier Fore. Research Center, J. Uriach & Cfa.S.A., Deg~ Bahf 59-67, 08026 Barcelona, Spain. Abstract: A new series of 4-(2-pyridyl)-2,2-dimethylnaphthalen-l-one potassium channel activators has been prepared and their in vitro relaxant activities in isolated rat portal vein and guinea-pig trachea as well as their hypotensive and bronchodilatory effects have been evaluated. Oxidation of the pyridyl nitrogen atom and a double bond between positions 3 and 4 provide compounds 14, which show some degree of airways selectivity.

PROTEIN KINASE C INHIBITORY ACTIVITIES OF BALANOL ANALOGS BEARING CARBOXYLIC ACID REPLACMENTS Julia M. Heerding*, John W. Lampe, James W. Darges and Mark L. Stamper.

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Bioorg. Med. Chem. Lett. 1995, 5, 1839 O

Departments of Chemical and Biomolecular Research, Sphinx Pharamaceuticals, A Division of Eli Lilly and Company, 4615 University Drive, Durham, North Carolina, 27707. Balanol analogs bearing carboxylic acid replacements (amides, sulfonamides, and tetrazoles) were synthesized and assayed as protein kinase C (PKC) inhibitors. Increased enzyme and isozyme selectivity, and cellular activity over the naturally occurring compound were realized.

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-- OH

O

(aN, 4~-(-)-balanol

RATIONAL DESIGN OF IRREVERSIBLE, PSEUDO-C2-SYMMETRIC Bioorg. Med. Chem. Lett. 1995, 5, 1843 HIV-I PROTEASE INHIBITORS. Chihyo Park, Jong Sung Koh, Young Chart Son, Ho-il Choi, Chang Sun Lee, Nakyen Choy, Kwang Yul Moon, Won Hee Jung, Sung Chun Kim*, Heungsik Yoon*, Biotech Research Institute, LG Chemical Ltd/ Research Park, P.O. Box 61 Yu Sung, Science Town, Taejon 305-380, Korea

Pseudo-C,-symmetric irreversible inhibitors of HIV-I protease containing cis-epoxJde such as 8 were developed. Ph

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Bioorg. Med. Chem. Lett. 1995, 5, 1849

[des His ~, des Phe 6, Glug]GLUCAGON AMIDE: A NEWLY DESIGNED "PURE" GLUCAGON ANTAGONIST Bassem Y. Azizeh, Brian A. Van Tine, Noel S. Sturm, Ann Marie Hutzler, Clinton David, Dev Trivedi and Victor J. Hruby* Department of Chemistry, University of Arizona, Tucson, Arizona 85721. We report the synthesis and biological activity of a new glucagon analog that was designed as a glucagon receptor antagonist. The new analog, [des His 1, des Phe 6, Glug]glucagon amide, was found to be a pure antagonist in a new more sensitive assay for partial agonist activity, with a binding potency ICs0 of 48 nM and a pA 2 value of 8.20.

1764

T I Bioorg. Med. Chem. Lett. 1995, 5, 1853

N-(QUINUCLIDIN-3-YL)-2-( 1 . M E T I t Y L - IH-INDOL.3-YL) -2-OXOACETAMIDE: A H I G H A F F I N I T Y 5-HT3 R E C E P T O R PARTIAL AGONIST R. D. Clark*, J. M. Muchowski, K. K. Weinhardt, M. P. Dillon, C-H. Lee, K. R. Bley, D. W. Bonhaus, E. H. F. Wong, and R. M. Eglen O Institutes o f Organic Chemistry and Pharmacology /~K ~ Syntex Research, Palo Alto, CA 94304 Abstract: The indolyl-2-oxoacetamide (R)-5 was found to be a high affinity 5-HT 3 receptor ligand (pK i = 9.6) that displayed partial agonist activity in functional assays

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N~ Me

N~

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Bioorg. Med. Chem. Lett. 1995, 5, 1857 2-SUBSTITUTED 2-AMINOETHANOL: MINIMUM ESSENTIAL [ STRUCTURE FOR IMMUNOSUPPRESSIVE ACTIVITY OF ISPol (MYRIOCIN) TetsuroFujita*.Ryoji Hirosea, NorimitsuHamamichi,Yuuki Kitaob, ShigeoSasakia, MasahikoYonetaa,andKenjiChiba': H2N .HCI Facu/t)"of PharmaceuticYdSciences. SetsunanUniversit),.45-1 NagaotogeHirakata Osaka573-01. Japan aResearch LzJboratory.TaitoCo.. Ltd.. 1-26HigashiShiriike-Shinmachi.Nagam-ku. Kobe653, Japan hFacult)"of PharmaceuticalSciences.Kvoto University,Sakyo-ku, Kvoto606-01.Japan HOH2C~,Q CResearchLaboratories. YoshitomiPharmaceuticalIndustries.Ltd.. 7-25Koyata3-chome. lrumashi, Saitama35R.Japan Abstruct: 2-Substituted2-aminoethanolwas shownto be the minimumessentialstructurelor the immunosuppressive activityof ISP-I (myritx:in.thermozymtx:idin)by simplificationof 2-substituted2-amino-1,3-propanediol,whichwas 08H17 generatedby modificationof ISP-I. Amongthe series,2-amino-4-(4-tYctylphenyl)butanolhydrochloridedisplayed comparablypotentactivityto 2-amino-2-[2-(4-octylphenyl)ethyll-1,3-propanediolhydrtx:hloride,FTY720.

I

[ Bioorg. Med. Chem. Lett. 1995, 5, 1861 HYDROXYLATION OF BENZENE BY HORSERADISH t PEROXIDASE AND IMMOBILIZED HORSERADISH PEROXIDASE IN AN ORGANIC SOLVENT. Reiko Akasaka, Tadahiko Mashino and Masaaki Hirobe, Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan Horseradish peroxidase and immobilized horseradish peroxidase catalyze hydroxylation of benzene when benzene was used as the reaction solvent. O

Horseradish Peroxidase or Immobilized Horseradish Peroxidase H2020rmCPBA - ~-OH in benzene containing a small amount of buffer

ANNOHEXOCIN, A NOVEL MONO-THF ACETOGENIN WITH SIX Bioorg. Med. Chem. Lett. 1995, 5, 1865 HYDROXYLS, FROM ANNONA MURICATA (ANNONACEAE) Lu Zeng, Feng-E Wu, and Jerry L. McLaughlin*, Department of,~ledicinal Chemistry amt Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue Universi(v, WestLafayette, IN 47907, U. S A Abstract: A novel acetogenin, annohexocin (1), was isolated from .4nnona muricata (Annonaceae) Compound 1 shinned significant bioactivities among six human solid tumor cell lines. 35 trans

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T The in vitro Cytotoxicity and DNA Alkylating Ability of the [

Med. Chem. Lett. 1995, 5, 1869

Bioorg.

Simplest F u n c t i o n a l A n a l o g u e s of the seco CC-1065 AIkylating Subunit Rodney H. Whitet, Peter G. Parsons , Arungundrum S. Prakash*§ and David J. Young*t. tFaculty of Science and Technology, Griffith University, Nathan, 4111, Australia; ~Queensland Institute of Medical Research, Herston, 4029; §National Research Centre for Environmental Toxicology, Kessels Rd, Coopers Plains, 4108. X

DNA

OH

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OH

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Bioorg. Med. Chem. Lett. 1995, 5, 1875 Design and Synthesis of a Conformationally Constrained Analog of the t Bis(heteroaryl)piperazine (BilAP) HIV-i Reverse Transeriptase Inhibitor Atevirdine

Michael J. Genin, ConnieG. Chidcster, DouglasC. Rohrer,and DonnaL. Romero* UpjohnLaboratories,Kalamazoo,MI 49lX)1. The designand synthesisof a novelconfonnationallyconstrainedspiroanalogue I of the BHAPclassof HIV-1 reverse transcriptase inhibitorsbasedon the X-raycrystalstructureof the clinicalcandidateatevirdineis described. Et

Mt<)~~.~......,.~ N~" ~ N- " ~ I ~ ' N ~H-

Et

McSO2NH~

H O N~,,/ Atcvirdine:ItydrogcnIxmdedconformationin crystalstructure.

1766

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