SAR profiles of spirocyclic nicotinamide derived selective HDAC1/HDAC2 inhibitors (SHI-1:2).


:A potent family of spirocyclic nicotinyl aminobenzamide selective HDAC1/HDAC2 inhibitors (SHI-1:2) is profiled. The incorporation of a biaryl zinc-binding motif into a nicotinyl scaffold resulted in enhanced potency and selectivity versus HDAC3, but also imparted hERG activity. It was discovered that increasing polar surface area about the spirocycle attenuates this liability. Compound 12 induced a 4-fold increase in acetylated histone H2B in an HCT-116 xenograft model study with acute exposure, and inhibited tumor growth in a 21-day efficacy study with qd dosing.


Bioorg Med Chem Lett


Methot JL,Hamblett CL,Mampreian DM,Jung J,Harsch A,Szewczak AA,Dahlberg WK,Middleton RE,Hughes B,Fleming JC,Wang H,Kral AM,Ozerova N,Cruz JC,Haines B,Chenard M,Kenific CM,Secrist JP,Miller TA




Has Abstract


2008-12-01 00:00:00














  • Evidence supporting the activity of 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentafuranosylcytosine as a terminator in enzymatic DNA-chain elongation.

    abstract::To investigate the stability of 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentafuranosylcytosine 3'-phosphoric acid, its thymidine ester was prepared via the phosphoramidite method using allyl protection for the phosphate function. This ester is stable under acidic conditions but extremely labile under basic conditions, de...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hayakawa Y,Kawai R,Otsuki K,Kataoka M,Matsuda A

    更新日期:1998-09-22 00:00:00

  • Synthesis, characterization and preliminary analysis of in vivo biological activity of chitosan/celecoxib microcapsules.

    abstract::The use of chitosan as the wall of microcapsule designed for delivery of encapsulated celecoxib is reported. Microcapsules were characterised with respect to size and encapsulation efficiency of celecoxib. In vivo animals demonstrated that both free celecoxib administration and chitosan/celecoxib microcapsules adminis...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Cheng SY,Yuen MC,Lam PL,Gambari R,Wong RS,Cheng GY,Lai PB,Tong SW,Chan KW,Lau FY,Kok SH,Lam KH,Chui CH

    更新日期:2010-07-15 00:00:00

  • Binding modes of 6,7 di-substituted 4-anilinoquinoline-3-carbonitriles to EGFR.

    abstract::4-Anilino-3-cyanoquinolines were reported to have irreversible binding to epidermal growth factor receptor kinase (EGFRK) by forming a covalent linkage to C773. Our initial docking studies gave results inconsistent with the in vitro data and showed two different binding modes. To perceive the exact mode of binding of ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Akula N,Bhalla J,Sridhar J,Pattabiraman N

    更新日期:2004-07-05 00:00:00

  • Discovery of anabaenopeptin 679 from freshwater algal bloom material: Insights into the structure-activity relationship of anabaenopeptin protease inhibitors.

    abstract::Cyanobacteria possess a unique capacity for the production of structurally novel secondary metabolites compared to the biosynthetic abilities of other environmental prokaryotes such as bacteria of the genus Streptomyces. Two different strategies to explore cyanobacteria-derived natural products have been explored prev...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Harms H,Kurita KL,Pan L,Wahome PG,He H,Kinghorn AD,Carter GT,Linington RG

    更新日期:2016-10-15 00:00:00

  • Adamantyl N-benzylbenzamide: new series of depigmentation agents with tyrosinase inhibitory activity.

    abstract::A new series of polyhydroxylated N-benzylbenzamide derivatives containing an adamantyl moiety has been synthesized, and the depigmenting and tyrosinase inhibitory activities of the molecules were evaluated. The lipophilic character of the adamantyl moiety appeared to confer greater depigmentation power on the benzamid...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Baek HS,Hong YD,Lee CS,Rho HS,Shin SS,Park YH,Joo YH

    更新日期:2012-03-01 00:00:00

  • The tert-butyl dimethyl silyl group as an enhancer of drug cytotoxicity against human tumor cells.

    abstract::In this study, we synthesized a series of enantiomerically pure (2R,3S)-disubstituted tetrahydropyranes with diverse functional groups using known methodologies. In addition to the tert-butyl dimethyl silyl group, other common protecting groups for hydroxyl groups such as allyl, acetate, and benzoate were used to obta...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Donadel OJ,Martín T,Martín VS,Villar J,Padrón JM

    更新日期:2005-08-01 00:00:00

  • Structure-based optimisation of 2-aminobenzylstatine derivatives: potent and selective inhibitors of the chymotrypsin-like activity of the human 20S proteasome.

    abstract::We have identified 2-aminobenzylstatine derivatives that inhibit non-covalently the chymotrypsin-like activity of the human 20S proteasome. A structure-based optimisation approach has allowed us to improve the potency of this structural class of proteasome inhibitors from micromolar to nanomolar level. The new derivat...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Furet P,Imbach P,Fuerst P,Lang M,Noorani M,Zimmermann J,García-Echeverría C

    更新日期:2002-05-20 00:00:00

  • Synthesis and antibacterial activity of 3-benzylamide derivatives as FtsZ inhibitors.

    abstract::The emergence and spread of multidrug-resistant strains of the human pathological bacteria are generating a threat to public health worldwide. In the current study, a series of PC190723 derivatives was synthesized and investigated for their antimicrobial activity. The compounds exhibited good activity against several ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Hu Z,Zhang S,Zhou W,Ma X,Xiang G

    更新日期:2017-04-15 00:00:00

  • (2R,3S)-(+)- and (2S,3R)-(-)-Halofuginone lactate: synthesis, absolute configuration, and activity against Cryptosporidium parvum.

    abstract::The trans-enantiomers of the commercially important anti-protozoal compound Halofuginone have been prepared and characterized, and the absolute configuration was assigned by X-ray crystallography. The activity of both enantiomers against Cryptosporidium parvum was determined in vitro and related to acute toxicity in v...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Linder MR,Heckeroth AR,Najdrowski M,Daugschies A,Schollmeyer D,Miculka C

    更新日期:2007-08-01 00:00:00

  • Discovery and optimization of a biphenylacetic acid series of prostaglandin D2 receptor DP2 antagonists with efficacy in a murine model of allergic rhinitis.

    abstract::Biphenylacetic acid (5) was identified through a library screen as an inhibitor of the prostaglandin D(2) receptor DP2 (CRTH2). Optimization for potency and pharmacokinetic properties led to a series of selective CRTH2 antagonists. Compounds demonstrated potency in a human DP2 binding assay and a human whole blood eos...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Scott JM,Baccei C,Bain G,Broadhead A,Evans JF,Fagan P,Hutchinson JH,King C,Lorrain DS,Lee C,Prasit P,Prodanovich P,Santini A,Stearns BA

    更新日期:2011-11-01 00:00:00

  • Synthesis and evaluation of novel phosphoramidate prodrugs of 2'-methyl cytidine as inhibitors of hepatitis C virus NS5B polymerase.

    abstract::A variety of new prodrugs of 2'-methyl cytidine based on acyloxy ethylamino phosphoramidates have been synthesized and tested in vitro and in vivo for their biological activity. Compared with the parent drug a 10- to 20-fold increase in formation of nucleotide triphosphate in rat and human hepatocytes could be achieve...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Donghi M,Attenni B,Gardelli C,Marco AD,Fiore F,Giuliano C,Laufer R,Leone JF,Pucci V,Rowley M,Narjes F

    更新日期:2009-03-01 00:00:00

  • Discovery of new chemotype dipeptidyl peptidase IV inhibitors having (R)-3-amino-3-methyl piperidine as a pharmacophore.

    abstract::Structures containing the (R)-3-amino-3-methyl piperidine unit as a new pharmacophore moiety have been shown to possess moderate inhibitory activity for DPP-4 with good pharmacokinetics profile. One of these compounds was found to have good oral bioavailability and PK/PD profile in ZF-rat. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Nishio Y,Kimura H,Tosaki S,Sugaru E,Sakai M,Horiguchi M,Masui Y,Ono M,Nakagawa T,Nakahira H

    更新日期:2010-12-15 00:00:00

  • Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B (PtpB) inhibitors: A polypharmacology strategy for treating Mycobacterium tuberculosis infections.

    abstract::Current treatments for Mycobacterium tuberculosis infections require long and complicated regimens that can lead to patient non-compliance, increasing incidences of antibiotic-resistant strains, and lack of efficacy against latent stages of disease. Thus, new therapeutics are needed to improve tuberculosis standard of...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Washburn A,Abdeen S,Ovechkina Y,Ray AM,Stevens M,Chitre S,Sivinski J,Park Y,Johnson J,Hoang QQ,Chapman E,Parish T,Johnson SM

    更新日期:2019-07-01 00:00:00

  • Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors.

    abstract::The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar subs...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Ng RA,Sun M,Bowers S,Hom RK,Probst GD,John V,Fang LY,Maillard M,Gailunas A,Brogley L,Neitz RJ,Tung JS,Pleiss MA,Konradi AW,Sham HL,Dappen MS,Adler M,Yao N,Zmolek W,Nakamura D,Quinn KP,Sauer JM,Bova MP,Ruslim

    更新日期:2013-08-15 00:00:00

  • Novel endoperoxides: synthesis and activity against Candida species.

    abstract::Fifteen new endoperoxides have been synthesised and tested for activity against pathogenic Candida species. These endoperoxides can be prepared in high yields, in one to three steps, from inexpensive starting materials. Despite chemical and structural similarities, their inhibitory activity against Candida growth vari...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Macreadie P,Avery T,Greatrex B,Taylor D,Macreadie I

    更新日期:2006-02-15 00:00:00

  • The binding of cocaine to cyclodextrins.

    abstract::Cocaine binds into beta-cyclodextrin, but not detectably into alpha- or gamma-cyclodextrin, in water solution. NMR studies indicate the geometry of the complex, which is confirmed by molecular mechanics calculations and binding studies on cocaine analogues and cyclodextrin dimers. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Nesna N,Lou J,Breslow R

    更新日期:2000-09-04 00:00:00

  • Potent 3-spiropiperidine growth hormone secretagogues.

    abstract::Systematic SAR studies of the different regioisomers and homologues of the spiro(indane-1,4-piperidine) moiety in the growth hormone secretagogue L-162,752 are presented. Among them, spiro(3H-1-benzopyran-2,3-piperidine) was found to afford secretagogues with low nanomolar in vitro activity. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Yang L,Morriello G,Prendergast K,Cheng K,Jacks T,Chan WW,Schleim KD,Smith RG,Patchett AA

    更新日期:1998-01-06 00:00:00

  • Synthesis of a Streptococcus pyogenes vaccine candidate based on the M protein PL1 epitope.

    abstract::Group A streptococcus is a Gram-positive bacteria that causes a range of infectious diseases. Targeting the bacteria, a new self-adjuvanting vaccine candidate, incorporating a carbohydrate carrier and an amino acid-based adjuvant, was synthesised utilising carbohydrate chemistry and solid-phase peptide synthesis proce...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Simerska P,Lu H,Toth I

    更新日期:2009-02-01 00:00:00

  • Synthesis and biological evaluation of sulfonamidooxazoles and beta-keto sulfones: selective inhibitors of 11beta-hydroxysteroid dehydrogenase type I.

    abstract::The design, synthesis, and biological evaluation of arylsulfonamidooxazoles as 11beta-HSD1 inhibitors and the serendipitous discovery of beta-keto sulfones as potent 11beta-HSD1 inhibitors are described here. These two classes of compounds are not active against 11beta-HSD2 and therefore may have significant therapeut...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Xiang J,Ipek M,Suri V,Massefski W,Pan N,Ge Y,Tam M,Xing Y,Tobin JF,Xu X,Tam S

    更新日期:2005-06-02 00:00:00

  • P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile.

    abstract::SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4, 4-dimethyl lactam as the new P4 cap unit with improved potency (K(i)( *)=15nM, EC 90=70nM) and pharmacokinetic properties...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Nair LG,Sannigrahi M,Bogen S,Pinto P,Chen KX,Prongay A,Tong X,Cheng KC,Girijavallabhan V,George Njoroge F

    更新日期:2010-01-15 00:00:00

  • 1,2,3-Triazoles as inhibitors of indoleamine 2,3-dioxygenase 2 (IDO2).

    abstract::Indoleamine 2,3-dioxygenase 2 (IDO2) is a potential therapeutic target for the treatment of diseases that involve immune escape such as cancer. In contrast to IDO1, only a very limited number of inhibitors have been described for IDO2 due to inherent difficulties in expressing and purifying a functionally active, solu...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Röhrig UF,Majjigapu SR,Caldelari D,Dilek N,Reichenbach P,Ascencao K,Irving M,Coukos G,Vogel P,Zoete V,Michielin O

    更新日期:2016-09-01 00:00:00

  • Hybrid anticancer agents: isothiocyanate-progesterone conjugates as chemotherapeutic agents and insights into their cytotoxicities.

    abstract::New hybrid molecules of isothiocyanate and progesterone and their metal complexes were synthesized exhibiting promising anti-proliferative and pro-apoptotic activity against breast and prostate cancer cells. These metal complex compounds exploited an existing cellular transport pathway for delivery of cytotoxic isothi...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Adsule S,Banerjee S,Ahmed F,Padhye S,Sarkar FH

    更新日期:2010-02-01 00:00:00

  • Radiosynthesis of PET radiotracer as a prodrug for imaging group II metabotropic glutamate receptors in vivo.

    abstract::Group II metabotropic glutamate receptors (mGluRs) have been implicated in a variety of neurological and psychiatric disorders in recent studies. As a noninvasive medical imaging technique and a powerful tool in neurological research, positron emission tomography (PET) offers the possibility to visualize and study gro...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wang JQ,Zhang Z,Kuruppu D,Brownell AL

    更新日期:2012-03-01 00:00:00

  • Evaluation of hadacidin analogues.

    abstract::Several derivatives of hadacidin have been developed and evaluated for activity against adenylosuccinate synthetase. ...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Tibrewal N,Elliott GI

    更新日期:2011-01-01 00:00:00

  • N-Heteroaryl glycinamides and glycinamines as potent NPY5 antagonists.

    abstract::Subtype specific ligands are needed to evaluate the therapeutic potential of modulating the brain's neuropeptide Y system. The benzothiazepine glycinamide 1a was identified as an NPY5 antagonist lead. While having acceptable solubility, the compound was found to suffer from high clearance and poor exposure. Optimizati...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Wu L,Lu K,Desai M,Packiarajan M,Joshi A,Marzabadi MR,Jubian V,Andersen K,Chandrasena G,Boyle NJ,Walker MW

    更新日期:2011-09-15 00:00:00

  • Cytotoxicity and DNA binding property of the dimers of triphenylethylene-coumarin hybrid with one amino side chain.

    abstract::Novel dimers of triphenylethylene-coumarin hybrid containing one amino side chain were designed and synthesized by the condensation of four dicarboxylic acids with the amino monomeric hybrids catalyzed by HATU and DIPEA at room temperature. The adding order of the reactants had a significant effect on the condensation...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Tan G,Yao Y,Gu Y,Li S,Lv M,Wang K,Chen H,Li X

    更新日期:2014-07-01 00:00:00

  • Discovery of triazolo [1,5-a] pyridine derivatives as novel JAK1/2 inhibitors.

    abstract::Small molecule JAK inhibitors have been demonstrated efficacy in rheumatoid arthritis, inflammatory bowel disease, and psoriasis with the approval of several drugs. Aiming to develop potent JAK1/2 inhibitors, two series of triazolo [1,5-a] pyridine derivatives were designed and synthesized by various strategies. The p...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Lu K,Wu W,Zhang C,Liu Z,Xiao B,Yuan Z,Li A,Chen D,Zhai X,Jiang Y

    更新日期:2020-07-15 00:00:00

  • An amide-based sulfenamide prodrug of gamma secretase inhibitor BMS-708163 delivers parent drug from an oral conventional solid dosage form in male beagle dog.

    abstract::The objective of this Letter is to report the first (to our knowledge) in vivo proof of concept for a sulfenamide prodrug to orally deliver a poorly soluble drug containing a weakly-acidic NH-acid from a conventional solid dosage formulation. This proof of concept was established using BMS-708163 (1), a gamma secretas...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Guarino VR,Olson RE,Everlof JG,Wang N,McDonald I,Haskell R,Clarke W,Lentz KA

    更新日期:2020-02-01 00:00:00

  • Synthesis and evaluation of a novel series of indoloisoquinolines as small molecule anti-malarial leads.

    abstract::A group of novel synthetic indoloisoquinolines was prepared and its potential as a novel series of small-molecule anti-malarial leads was assessed. The structure-activity relationship on variation of three distinct regions of chemical space was investigated. A lead compound was generated with an activity close to that...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Horrocks P,Fallon S,Denman L,Devine O,Duffy LJ,Harper A,Meredith EL,Hasenkamp S,Sidaway A,Monnery D,Phillips TR,Allin SM

    更新日期:2012-02-15 00:00:00

  • Protection of a single-cysteine redox switch from oxidative destruction: On the functional role of sulfenyl amide formation in the redox-regulated enzyme PTP1B.

    abstract::Model reactions offer a chemical mechanism by which formation of a sulfenyl amide residue at the active site of the redox-regulated protein tyrosine phosphatase PTP1B protects the cysteine redox switch in this enzyme against irreversible oxidative destruction. The results suggest that 'overoxidation' of the sulfenyl a...

    journal_title:Bioorganic & medicinal chemistry letters

    pub_type: 杂志文章


    authors: Sivaramakrishnan S,Cummings AH,Gates KS

    更新日期:2010-01-15 00:00:00