- Spirocyclic sulfonamides with carbonic anhydrase inhibitory and anti-neuropathic pain activity
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A novel series of 4-oxo-spirochromane bearing primary sulfonamide group were synthetized as Carbonic Anhydrase inhibitors (CAIs) and tested for their management of neuropathic pain. Indeed, CAs have been recently validated as novel therapeutic targets in neuropathic pain. All compounds, here reported, showed strong activity against hCA II and hCA VII with KI values in the low or sub-nanomolar range. Two compounds (6d and 6l) showed good neuropathic pain attenuating effects and longer duration than drug reference acetazolamide in an animal model of oxaliplatin induced neuropathy.
- Kalisha Vali,Gundla, Rambabu,Singh, Om V.,Tamboli, Yasinalli,Di Cesare Manelli, Lorenzo,Ghelardini, Carla,Al-Tamimi, Abdul-Malek S.,Carta, Fabrizio,Angeli, Andrea,Supuran, Claudiu T.
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Read Online
- DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors
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We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11 was highly bio-available, crystalline 11 was poorly soluble and suffered disappointingly low bio-availability because of solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining crystalline 31 proved problematic, however; thus salt screening was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bio-available crystalline tris-salt 32. IDO1 inhibitor 32 is characterized by a low calculated human dose, best-in-class potential, and an unusual inhibition mode by binding the IDO1 heme-free (apo) form.
- Kazmierski, Wieslaw M.,Xia, Bing,Miller, John,De La Rosa, Martha,Favre, David,Dunham, Richard M.,Washio, Yoshiaki,Zhu, Zhengrong,Wang, Feng,Mebrahtu, Makda,Deng, Hongfeng,Basilla, Jonathan,Wang, Liping,Evindar, Ghotas,Fan, Lijun,Olszewski, Alison,Prabhu, Ninad,Davie, Christopher,Messer, Jeffrey A.,Samano, Vicente
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Read Online
- From PARP1 to TNKS2 inhibition: A structure-based approach
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Tankyrases (TNKSs) have recently gained great consideration as potential targets in Wnt/β-catenin pathway-dependent solid tumors. Previously, we reported the 2-mercaptoquinazolin-4-one MC2050 as a micromolar PARP1 inhibitor. Here we show how the resolution of the X-ray structure of PARP1 in complex with MC2050, combined with the computational investigation of the structural differences between TNKSs and PARP1/2 active sites, provided the rationale for a structure-based drug design campaign that with a limited synthetic effort led to the discovery of the bis-quinazolinone 5 as a picomolar and selective TNKS2 inhibitor, endowed with antiproliferative effects in a colorectal cancer cell line (DLD-1) where the Wnt pathway is constitutively activated.
- Tomassi, Stefano,Pfahler, Julian,Mautone, Nicola,Rovere, Annarita,Esposito, Chiara,Passeri, Daniela,Pellicciari, Roberto,Novellino, Ettore,Pannek, Martin,Steegborn, Clemens,Paiardini, Alessandro,Mai, Antonello,Rotili, Dante
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supporting information
p. 862 - 868
(2020/06/30)
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- Spirocyclic compound containing pyrimidine and application thereof
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The invention discloses a pyrimidine-containing spiro compound, structure as shown in a general formula I : The compound of the invention has a broad-spectrum bactericidal activity . and has an excellent control effect, on cucumber downy mildew, wheat powdery mildew, corn rust, rice blast, cucumber anthracnose and the like.
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Paragraph 0146-0149
(2020/03/17)
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- Design, Synthesis, and Structure-Activity Relationship of Novel Spiropyrimidinamines as Fungicides against Pseudoperonospora cubensis
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Harmful fungus and the developed resistance to available fungicides seriously threaten the yield and quality of crops; thus, the search for new, highly efficient, and resistance-overcoming fungicides remains a quite urgent goal of agricultural scientists. In this study, a series of novel spiropyrimidinamine derivatives were designed and synthesized by employing the intermediate derivatization method (IDM). Their structures were identified by 1H NMR, elemental analyses, and MS spectra. The structure of compound 5 was further confirmed by X-ray diffraction. Bioassays indicated that a number of the title compounds exhibited some fungicidal activities against Pseudoperonospora cubensis. Especially, compound 5 displayed excellent activity (EC50 = 0.422 mg/L), significantly higher than those of the commercialized fungicides cyazofamid, flumorph, and diflumetorim. The structure-activity relationship was also discussed. It was concluded that compound 5 with super fungicidal potency and a novel structure is a promising agrochemical fungicide candidate for further development.
- Guan, Aiying,Li, Zhinian,Liu, Changling,Yang, Jinlong,Zhang, Pengfei
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p. 6485 - 6492
(2020/07/08)
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- Whole cell screen based identification of spiropiperidines with potent antitubercular properties
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Abstract Whole cell based screens to identify hits against Mycobacterium tuberculosis (Mtb), carried out under replicating and non-replicating (NRP) conditions, resulted in the identification of multiple, novel but structurally related spiropiperidines with potent antitubercular properties. These compounds could be further classified into three classes namely 3-(3-aryl-1,2,4-oxadiazol-5-yl)-1′-alkylspiro[indene-1,4′-piperidine] (abbr. spiroindenes), 4-(3-aryl-1,2,4-oxadiazol-5-yl)-1′-alkylspiro[chromene-2,4′-piperidine] (abbr. spirochromenes) and 1′-benzylspiro[indole-1,4′-piperidin]-2(1H)-one (abbr. spiroindolones). Spiroindenes showed ≥4 log10 kill (at 2-12 μM) on replicating Mtb, but were moderately active under non replicating conditions. Whole genome sequencing efforts of spiroindene resistant mutants resulted in the identification of I292L mutation in MmpL3 (Mycobacterial membrane protein Large), required for the assembly of mycolic acid into the cell wall core of Mtb. MIC modulation studies demonstrated that the mutants were cross-resistant to spirochromenes but not to spiroindolones. This Letter describes lead identification efforts to improve potency while reducing the lipophilicity and hERG liabilities of spiroindenes. Additionally, as deduced from the SAR studies, we provide insights regarding the new chemical opportunities that the spiroindolones can offer to the TB drug discovery initiatives.
- Tantry, Subramanyam J.,Degiacomi, Giulia,Sharma, Sreevalli,Jena, Lalit Kumar,Narayan, Ashwini,Guptha, Supreeth,Shanbhag, Gajanan,Menasinakai, Sreenivasaiah,Mallya, Meenakshi,Awasthy, Disha,Balakrishnan, Gayathri,Kaur, Parvinder,Bhattacharjee, Deepa,Narayan, Chandan,Reddy, Jitendar,Naveen Kumar,Shandil, Radha,Boldrin, Francesca,Ventura, Marcello,Manganelli, Riccardo,Hartkoorn, Ruben C.,Cole, Stewart T.,Panda, Manoranjan,Markad, Shankar D.,Ramachandran, Vasanthi,Ghorpade, Sandeep R.,Dinesh, Neela
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supporting information
p. 3234 - 3245
(2015/07/08)
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- Synthesis, biological evaluation and molecular docking studies of piperidinylpiperidines and spirochromanones possessing quinoline moieties as Acetyl-CoA carboxylase inhibitors
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Acetyl-coenzyme A carboxylases (ACCs) play critical roles in the regulation of fatty acid metabolism and have been targeted for the development of drugs against obesity, diabetes and other metabolic diseases. Two series of compounds possessing quinoline moieties were designed, synthesized and evaluated for their potential to inhibit acetyl-CoA carboxylases. Most compounds showed moderate to good ACC inhibitory activities and compound 7a possessed the most potent biological activities against ACC1 and ACC2, with IC50 values of 189 nM and 172 nM, respectively, comparable to the positive control. Docking simulation was performed to position compound 7a into the active site of ACC to determine a probable binding model.
- Huang, Tonghui,Sun, Jie,Wang, Qianqian,Gao, Jian,Liu, Yi
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p. 16221 - 16234
(2015/12/01)
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- Synthesis and pharmacological evaluation of novel N-aryl-3,4-dihydro- 1′H-spiro[chromene-2,4′-piperidine]-1′-carboxamides as TRPM8 antagonists
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A novel series of N-aryl-3,4-dihydro-1′H-spiro[chromene-2,4′- piperidine]-1′-carboxamides was identified as transient receptor potential melastatin 8 (TRPM8) channel blockers through analogue-based rational design, synthesis and screening. Details of the synthesis, effect of aryl groups and their substituents on in-vitro potency were studied. The effects of selected functional groups on the 4-position of the chromene ring were also studied, which showed interesting results. The 4-hydroxy derivatives showed excellent potency and selectivity. Optical resolution and screening of alcohols revealed that (R)-(-)-isomers were in general more potent than the corresponding (S)-(+)-isomers. The isomer (R)-(-)-10e (IC50: 8.9 nM) showed a good pharmacokinetic profile upon oral dosing at 10 mg/kg in Sprague-Dawley (SD) rats. The compound (R)-(-)-10e also showed excellent efficacy in relevant rodent models of neuropathic pain.
- Chaudhari, Sachin S.,Kadam, Ashok B.,Khairatkar-Joshi, Neelima,Mukhopadhyay, Indranil,Karnik, Pallavi V.,Raghuram, Anupindi,Rao, Shobha S.,Vaiyapuri, Thamil Selvan,Wale, Dinesh P.,Bhosale, Vikram M.,Gudi, Girish S.,Sangana, Ramchandra R.,Thomas, Abraham
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p. 6542 - 6553
(2013/10/22)
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- CHROMAN - SPIROCYCLIC PIPERIDINE AMIDES AS MODULATORS OF ION CHANNELS
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The invention relates to chroman spirocyclic piperidine amide derivatives useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
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Page/Page column 67
(2012/09/10)
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- NOVEL SPIRO COMPOUNDS USEFUL AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE
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Heteroaromatic compounds of structural formula (I) are selective inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD1) relative to other known stearoyl-coenzyme A desaturases. The compounds of the present invention are useful for the prevention and
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Page/Page column 49
(2011/02/24)
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- NOVEL SPIRO COMPOUNDS USEFUL AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE
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Heteroaromatic compounds of structural formula (I) are selective inhibitors of stearoyl-coenzyme A delta-9 desat- urase (SCD1) relative to other known stearoyl-coenzyme A desaturases. The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease, such as atherosclerosis; obesity; diabetes; neurological disease; metabolic syndrome; insulin resistance; and liver steatosis.
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Page/Page column 114-115
(2010/09/17)
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- Synthesis and evaluation of novel stearoyl-CoA desaturase 1 inhibitors: 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3, 4-dihydrospiro[chromene-2,4′-piperidine] analogs
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In continuation of our investigation on novel stearoyl-CoA desaturase (SCD) 1 inhibitors, we have already reported on the structural modification of the benzoylpiperidines that led to a series of novel and highly potent spiropiperidine-based SCD1 inhibitors. In this report, we would like to extend the scope of our previous investigation and disclose details of the synthesis, SAR, ADME, PK, and pharmacological evaluation of the spiropiperidines with high potency for SCD1 inhibition. Our current efforts have culminated in the identification of 5-fluoro-1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol- 2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine] (10e), which demonstrated a very strong potency for liver SCD1 inhibition (ID 50 = 0.6 mg/kg). This highly efficacious inhibition is presumed to be the result of a combination of strong enzymatic inhibitory activity (IC 50 (mouse) = 2 nM) and good oral bioavailability (F >95%). Pharmacological evaluation of 10e has demonstrated potent, dose-dependent reduction of the plasma desaturation index in C57BL/6J mice on a high carbohydrate diet after a 7-day oral administration (q.d.). In addition, it did not cause any noticeable skin abnormalities up to the highest dose (10 mg/kg).
- Uto, Yoshikazu,Ueno, Yuko,Kiyotsuka, Yohei,Miyazawa, Yuriko,Kurata, Hitoshi,Ogata, Tsuneaki,Yamada, Makiko,Deguchi, Tsuneo,Konishi, Masahiro,Takagi, Toshiyuki,Wakimoto, Satoko,Ohsumi, Jun
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supporting information; experimental part
p. 4788 - 4796
(2010/12/18)
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- Novel spiropiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine]
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Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6 J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6 J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3 mg/kg) in our preliminary analysis.
- Uto, Yoshikazu,Kiyotsuka, Yohei,Ueno, Yuko,Miyazawa, Yuriko,Kurata, Hitoshi,Ogata, Tsuneaki,Deguchi, Tsuneo,Yamada, Makiko,Watanabe, Nobuaki,Konishi, Masahiro,Kurikawa, Nobuya,Takagi, Toshiyuki,Wakimoto, Satoko,Kono, Keita,Ohsumi, Jun
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supporting information; scheme or table
p. 746 - 754
(2010/06/11)
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- Synthesis of spiro[chroman-2,4′-piperidin]-4-one derivatives as acetyl-CoA carboxylase inhibitors
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Various spiro[chroman-2,4′-piperidin]-4-one derivatives (38a-m and 43a-j) have been designed, synthesized and evaluated for in vitro acetyl-CoA carboxylase (ACC) inhibitory activity. Several compounds have shown ACC inhibitory activity in low nanomolar ra
- Shinde, Pundlik,Srivastava, Sanjay K.,Odedara, Rajendra,Tuli, Davinder,Munshi, Siralee,Patel, Jitendra,Zambad, Shitalkumar P.,Sonawane, Rajesh,Gupta, Ramesh C.,Chauthaiwale, Vijay,Dutt, Chaitanya
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scheme or table
p. 949 - 953
(2009/08/15)
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- Spirocyclic delta opioid receptor agonists for the treatment of pain: Discovery of N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4′-piperidine]-4- yl) benzamide (ADL5747)
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Selective, nonpeptidic δ opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.
- Bourdonnec, Bertrand Le,Windh, Rolf T.,Leister, Lara K.,Zhou, Q. Jean,Ajello, Christopher W.,Gu, Minghua,Chu, Guo-Hua,Tuthill, Paul A.,Barker, William M.,Koblish, Michael,Wiant, Daniel D.,Graczyk, Thomas M.,Belanger, Serge,Cassel, Joel A.,Feschenko, Marina S.,Brogdon, Bernice L.,Smith, Steven A.,Derelanko, Michael J.,Kutz, Steve,Little, Patrick J.,Dehaven, Robert N.,DeHaven-Hudkins, Diane L.,Dolle, Roland E.
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experimental part
p. 5685 - 5702
(2010/02/28)
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- SPIROKETONE ACETYL-COA CARBOXYLASE INHIBITORS
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The invention provides compounds of Formula (1) or a pharmaceutically acceptable salt of said compound, wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating mammals suffering from the condition of being overweight.
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(2008/12/06)
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- Potent, orally bioavailable delta opioid receptor agonists for the treatment of pain: Discovery of N,N-diethyl-4-(5-hydroxyspiro-[chromene-2, 4′-piperidine]-4-yl)benzamide (ADL5859)
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Selective δ opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable δ agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.
- Le Bourdonnec, Bertrand,Windh, Rolf T.,Ajello, Christopher W.,Leister, Lara K.,Gu, Minghua,Chu, Guo-Hua,Tuthill, Paul A.,Barker, William M.,Koblish, Michael,Wiant, Daniel D.,Graczyk, Thomas M.,Belanger, Serge,Cassel, Joel A.,Feschenko, Marina S.,Brogdon, Bernice L.,Smith, Steven A.,Christ, David D.,Derelanko, Michael J.,Kutz, Steve,Little, Patrick J.,DeHaven, Robert N.,DeHaven-Hudkins, Diane L.,Dolle, Roland E.
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supporting information; experimental part
p. 5893 - 5896
(2009/10/17)
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- N-sulfamoyl-N'-benzopyranpiperidine compounds and uses thereof
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N-sulfamoyl-N′-benzopyranpiperidine compounds of formula I and their physiologically acceptable acid addition salts, pharmaceutical compositions comprising them, processes for their preparation, and their use for the treatment and/or inhibition of glaucoma, epilepsy, bipolar disorders, migraine, neuropathic pain, obesity, type II diabetes, metabolic syndrome, alcohol dependence, and/or cancer, and related concomitant and/or secondary diseases or conditions.
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Page/Page column 14
(2008/06/13)
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- N-SULFAMOYL-N’-BENZOPYRANPIPERIDINES AS INHBITORS OF CARBONIC ANHYDRASES
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The present invention relates to novel N-sulfamoyl-N'-benzopyranpiperidines of general formula (I) and their physiologically acceptable acid addition salts, to pharmaceutical compositions comprising them, processes for their preparation, and their use for the prophylaxis and/or treatment and/or prevention and/or inhibition of glaucoma, epilepsy, bipolar disorders, migraine, neuropathic pain, obesity, type II diabetes, metabolic syndrome, alcohol dependence, and/or cancer, and its concomitant and/or secondary diseases or conditions.
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Page/Page column 30
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- SPIROCYCLIC HETEROCYCLIC DERIVATIVES AND METHODS OF THEIR USE
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Spirocyclic heterocyclic derivatives, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the spirocyclic heterocyclic derivatives are ligands of the δ opioid receptor and may be useful, inter alia, for treating and/or preventing pain, anxiety, gastrointestinal disorders, and other δ opioid receptor-mediated conditions.
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Page/Page column 142; 288288
(2008/06/13)
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- New synthesis of flavanones catalyzed by L-proline
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L-Proline is utilized as an efficient organocatalyst for the synthesis of substituted flavanones and chalcones in good yields. The efficiency of the catalyst was proved with a variety of substrates ranging from electron-deficient to electron-rich aryl aldehydes and 2-hydroxyacetophenones.
- Chandrasekhar,Vijeender,Venkatram Reddy
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p. 6991 - 6993
(2007/10/03)
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- SPIROCYCLIC HETEROCYCLIC DERIVATIVES AND METHODS OF THEIR USE
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Spirocyclic heterocyclic derivatives, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the spirocyclic heterocyclic derivatives are ligands of the δ opioid receptor and
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Page/Page column 472
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