- An efficient synthesis of nilotinib (AMN107)
-
A concise synthesis of AMN107, a compound currently undergoing several phase II/III clinical trials for chronic myelogenous leukemia is described. The new procedure reduces the number of synthetic steps from eight to four, with an overall yield of 65%. Georg Thieme Verlag Stuttgart.
- Huang, Wei-Sheng,Shakespeare, William C.
-
-
Read Online
- Discovery of a Candidate Containing an (S)-3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1 H-inden Scaffold as a Highly Potent Pan-Inhibitor of the BCR-ABL Kinase including the T315I-Resistant Mutant for the Treatment of Chronic Myeloid Leukemia
-
BCR-ABL kinase inhibition is an effective strategy for the treatment of chronic myeloid leukemia (CML). Herein, we report compound 3a-P1, bearing a difluoro-indene scaffold, as a novel potent pan-inhibitor against BCR-ABL mutants, including the most refractory T315I mutant. As the privileged (S)-isomer compared to its (R)-isomer 3a-P2, 3a-P1 exhibited potent antiproliferative activities against K562 and Ku812 CML cells and BCR-ABL and BCR-ABLT315I BaF3 cells, with IC50 values of 0.4, 0.1, 2.1, and 4.7 nM, respectively. 3a-P1 displayed a good safety profile in a battery of assays, including single-dose toxicity, hERG K+, and genotoxicity. It also showed favorable mice pharmacokinetic properties with a good oral bioavailability (32%), a reasonable half-life (4.61 h), and a high exposure (1386 h·ng/mL). Importantly, 3a-P1 demonstrated a higher potency than ponatinib in a mice xenograft model of BaF3 harboring BCR-ABLT315I. Overall, the results indicate that 3a-P1 is a promising drug candidate for the treatment of CML to overcome the imatinib-resistant T315I BCR-ABL mutation.
- Zhang, Dongfeng,Li, Peng,Gao, Yongxin,Song, Yaoyao,Zhu, Yaqin,Su, Hong,Yang, Beibei,Li, Li,Li, Gang,Gong, Ningbo,Lu, Yang,Shao, Huanjie,Yu, Chunrong,Huang, Haihong
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p. 7434 - 7452
(2021/06/25)
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- Discovery of Potent Antiallergic Agents Based on ano-Aminopyridinyl Alkynyl Scaffold
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Effective therapeutic agents are highly desired for immune-mediated allergic diseases. Herein, we report the design, synthesis, and structure-activity relationship of ano-aminopyridinyl alkyne series as novel orally bioavailable antiallergic agents, which
- Bai, Fang,Chen, Taiwen,Fan, Chen,Hu, Youhong,Li, Xin,Liu, Moting,Ma, Yanjie,Tang, Wei,Xiang, Caigui,Xie, Zhicheng
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supporting information
p. 13588 - 13603
(2021/09/20)
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- COMPOUNDS USEFUL FOR INHIBITING RAF DIMERS
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The disclosure provides compounds of Formula I (Formula I) (c) And the pharmaceutically acceptable salts thereof. The A, B, C, and D rings and the variables, RA, RB, RC, RD, L0, L1, L2
- -
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Paragraph 0151; 0152
(2020/09/12)
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- Accelerated Discovery of Novel Ponatinib Analogs with Improved Properties for the Treatment of Parkinson's Disease
-
Parkinson's disease (PD) is a debilitating and common neurodegenerative disease. New insights implicating c-Abl activation as a driving force in PD have opened a new drug development avenue for PD treatment beyond the symptomatic relief by L-DOPA. BCR-Abl inhibitors, which include nilotinib and ponatinib, have been found to inhibit this process, and nilotinib has shown improvement in outcomes in a 12-patient, nonrandomized trial. However, nilotinib is a potent inhibitor of hERG, a cardiac K+ channel whose inhibition increases risk of sudden death. We used our machine learning approach to predict novel molecules that would inhibit c-Abl while also having minimal liability against hERG. Of our six novel compounds tested, we identified two that had c-Abl potencies comparable to nilotinib, but with significantly improved profiles regarding the hERG channel. Our best compound exhibited a hERG IC50 of 12.1 μM (compared to nilotinib with an IC50 of 0.45 μM and ponatinib with IC50 of 0.767 μM). This work is a step forward for a machine learning enabled, multiparameter optimization of a chemical space and represents a significant advance in the development of novel Parkinson's therapies.
- Kaiser, Thomas M.,Dentmon, Zackery W.,Dalloul, Christopher E.,Sharma, Savita K.,Liotta, Dennis C.
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supporting information
p. 491 - 496
(2020/04/30)
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- ABELSON NON-TYROSINE KINASE COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
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The present disclosure relates to compounds for the use of treating neurodegenerative diseases and, in particular, to compounds targeting the Abelson non-tyrosine kinase (c-Abl) protein for such treatment. The neurological disorders and conditions include Parkinson's disease, Alzheimer's disease and the like. It also relates to pharmaceutical compositions and methods of treatment of such neurological disorders involving the c-Abl protein kinase.
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Page/Page column 8; 19-20; 24; 28
(2020/10/28)
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- Novel substituted benzoyl compound and its pharmaceutically acceptable salt and preparation method and application (by machine translation)
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The invention relates to the general formula I shown novel substituted benzoyl compound and its pharmaceutically acceptable salt and preparation method and application. The invention also provides pharmaceutical compositions containing them, in vitro and in vivo anti-tumor effect results and acute toxicity study, the obtained anti-tumor drug model substituted benzoyl compound, has more excellent anti-tumor activity and safety, can be in the treatment of leukemia, lung cancer, colon cancer, ovarian cancer and renal carcinoma tumor in the application, so that the therapeutic window, so in the medical field as antitumor agents in the very application value. (by machine translation)
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Paragraph 0045; 0048; 0058-0059
(2019/11/13)
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- Novel S-type or R-type tetrahydronaphthalene amide compounds and pharmaceutically acceptable salts thereof, and preparation method and application thereof
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The invention relates to novel S-type or R-type tetrahydronaphthalene amide compounds and pharmaceutically acceptable salts thereof, and a preparation method and application thereof. The novel S-typeor R-type tetrahydronaphthalene amide compounds and the
- -
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Paragraph 0158; 0175-0177
(2019/11/29)
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- AMINOTHIAZOLE COMPOUNDS AS C-KIT INHIBITORS
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The invention relates to c-Kit inhibitors useful in the treatment of cancers, and other -threonine kinase mediated diseases, having the Formula: (I) wherein A, L, R1, R2, R3, and n are described herein.
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Page/Page column 00259
(2018/07/05)
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- Substituted tetrahydronaphthalene naphthalimide compound and its pharmaceutically acceptable salt and preparation method and application (by machine translation)
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The invention relates to the general formula I shown in the naphthalimide substituted tetrahydronaphthalene amine compounds and their pharmaceutically acceptable salt and preparation method and application. As an anti-tumor drug, the invention also provid
- -
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Paragraph 0068; 0084; 0085; 0086
(2017/08/25)
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- Discovery of novel Ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors
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FGF receptors (FGFRs) are tyrosine kinases that are overexpressed in diverse tumors by genetic alterations such as gene amplifications, somatic mutations and translocations. Owing to this characteristic, FGFRs are attractive targets for cancer treatment. It has been demonstrated that most multi-targeted, ATP competitive tyrosine kinase inhibitors are active against FGFRs as well as other kinases. The design of new and more selective inhibitors of FGFRs, which might be reduced off-target and side effects, is a difficult yet significant challenge. The results of the current investigation, show that novel Ponatinib analogues are highly active as FGFR inhibitors and that they possess reduced kinase insert domain receptor (KDR) activities. Observations made in a structure and activity relationship (SAR) investigation led to the development of a promising, orally available lead compound 4, which displays a 50–100 fold in vitro selectivity for inhibition of FGFR1-3 over KDR. In addition, biological evaluation of compound 4 showed that it displays significant antitumor activities in FGFR1-amplificated H1581 and FGFR2-amplificated SNU-16 xenograft models.
- Liu, Yang,Peng, Xia,Guan, Xiaocong,Lu, Dong,Xi, Yong,Jin, Shiyu,Chen, Hui,Zeng, Limin,Ai, Jing,Geng, Meiyu,Hu, Youhong
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p. 122 - 132
(2016/10/25)
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- BCR-ABL DIPLOID INHIBITOR, PREPARATION METHOD THEREFOR, AND USES THEREOF
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Disclosed are compounds or pharmaceutically acceptable salts thereof having the following general formula: R-Linker-R. The compounds or pharmaceutically acceptable salts thereof provided by the present invention are used as Bcr-Abl diploid inhibitors, whi
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Paragraph 0048
(2017/03/08)
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- Preparation and application of oxadiazole compound
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The invention provides preparation and application of an oxadiazole compound. The preparation method comprises the steps of: adding a first compound and a second compound into a container, and conducting reacting under the action of K2CO3 and THF (Tetrahy
- -
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Paragraph 0066; 0067; 0068
(2017/07/19)
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- From Lead to Drug Candidate: Optimization of 3-(Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Derivatives as Agents for the Treatment of Triple Negative Breast Cancer
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Herein we report the sophisticated process of structural optimization toward a previously disclosed Src inhibitor, compound 1, which showed high potency in the treatment of triple negative breast cancer (TNBC) both in vitro and in vivo but had considerable toxicity. A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were synthesized. In vitro cell-based phenotypic screening together with in vivo assays and structure-activity relationship (SAR) studies finally led to the discovery of N-(3-((4-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (13an). 13an is a multikinase inhibitor, which potently inhibited Src (IC50 = 0.003 μM), KDR (IC50 = 0.032 μM), and several kinases involved in the MAPK signal transduction. This compound showed potent anti-TNBC activities both in vitro and in vivo, and good pharmacokinetic properties and low toxicity. Mechanisms of action of anti-TNBC were also investigated. Collectively, the data obtained in this study indicate that 13an could be a promising drug candidate for the treatment of TNBC and hence merits further studies.
- Zhang, Chun-Hui,Chen, Kai,Jiao, Yan,Li, Lin-Li,Li, Ya-Ping,Zhang, Rong-Jie,Zheng, Ming-Wu,Zhong, Lei,Huang, Shen-Zhen,Song, Chun-Li,Lin, Wan-Ting,Yang, Jiao,Xiang, Rong,Peng, Bing,Han, Jun-Hong,Lu, Guang-Wen,Wei, Yu-Quan,Yang, Sheng-Yong
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supporting information
p. 9788 - 9805
(2016/11/19)
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- PROCESSES FOR MAKING PONATINIB AND INTERMEDIATES THEREOF
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Methods are disclosed for making 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-l-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide, intermediates and pharmaceutically acceptable salts thereof.
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Page/Page column 14; 15
(2016/12/26)
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- CELL-PERMEABLE, CELL-COMPATIBLE, AND CLEAVABLE LINKERS FOR COVALENT TETHERING OF FUNCTIONAL ELEMENTS
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Provided herein are cell-permeable, cell-compatible, and chemoselectively-cleavable linkers for tethering (e.g., covalently) functional elements (e.g., a cellular interaction element and a capture element), and methods of use (e.g., intracellular capture and extracellular release of cellular targets) therewith.
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Paragraph 0252-0253
(2016/12/22)
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- A drug treating chronic granulocytic leukemia method for the preparation of
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The invention relates to a preparation method of a drug for treating chronic granulocytic leukemia, belonging to the field of medical chemistry, and specifically relates to a preparation method of 3-[2-(imidazo[1,2-b] pyridazine-3-yl) acetenyl]-4-methyl-N
- -
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Paragraph 0045; 0046
(2017/04/28)
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- Hybrid pyrimidine alkynyls inhibit the clinically resistance related Bcr-AblT315I mutant
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abstract A series of pyrimidine alkynyl derivatives were designed and synthesized as new Bcr-Abl inhibitors by hybriding the structural moieties from GNF-7, ponatinib and nilotinib. One of the most potent compounds 4e strongly suppresses Bcr-AblWT and Bcr-AblT315I kinase with IC50 values of 5.0 and 9.0 nM, and inhibits the proliferation of K562 and murine Ba/F3 cells ectopically expressing Bcr-AblT315I cells with IC50 values of 2 and 50 nM, respectively. It also displays good pharmacokinetics properties with an oral bioavailability of 35.3% and T1/2 value of 48.7 h, and demonstrates significantly suppression on tumor growth in xenografted mice of K562 and Ba/F3 cells expressing Bcr-AblT315I. These inhibitors may serve as lead compounds for further developing new anticancer drugs overcoming the clinically acquired resistance against current Bcr-Abl inhibitors.
- Lu, Xiaoyun,Zhang, Zhang,Ren, Xiaomei,Pan, Xiaofeng,Wang, Deping,Zhuang, Xiaoxi,Luo, Jingfeng,Yu, Rongmin,Ding, Ke
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supporting information
p. 3458 - 3463
(2015/08/06)
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- Relative Rate Profiles of Functionalized Iodoarene Catalysts for Iodine(III) Oxidations
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A series of rate studies were conducted to evaluate the steric and electronic properties that govern the reactivity of iodoarene amide catalysts in the α-oxytosylation of propiophenone. A meta-substituted benzamide catalyst emerged as the most reactive. This catalyst was employed in the α-oxytosylation of a series of substituted propiophenones, returning the α-tosyloxy ketone products in excellent isolated yield.
- Lex, Timothy R.,Swasy, Maria I.,Whitehead, Daniel C.
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p. 12234 - 12243
(2016/01/09)
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- 1H-1,8- NAPHTHYRIDIN-2ONES AS ANTI PROLIFERATIVE COMPOUNDS
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The present invention relates to novel antiproliferative1H-1, 8-naphthyridin-2-ones of the general formula (I) or pharmaceutically acceptable salts thereof: In which the variable groups are as defined herein, and their preparation and use in therapeutic treatment of disorders related to inhibition of tyrosine kinases in warm blooded animals. The compounds can overcome imatinib induced drug resistance.
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Page/Page column 30
(2015/12/30)
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- PROCESSES FOR MAKING PONATINIB AND INTERMEDIATES THEREOF
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Novel synthetic approaches to make 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide, intermediates and pharmaceutically acceptable salts thereof are provided.
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Paragraph 0074; 0078
(2014/12/09)
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- PROTEIN KINASE INHIBITORS (VARIANTS), USE THEREOF IN TREATING ONCOLOGICAL DISEASES AND A PHARMACEUTICAL COMPOSITION BASED THEREON
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The present invention relates to the treatment of oncological, chronic inflammatory and similar diseases with the aid of new families of chemical compounds having improved efficiency with regard to the inhibition of Abl kinase and mutant forms thereof, as well as other therapeutically significant kinases. It describes protein kinase inhibitors in the form of compounds of general formula (I) and compounds of general formula (II), or a tautomer, an individual isomer, a mixture of isomers, a pharmaceutically acceptable salt, a solvate or a hydrate thereof.
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Page/Page column
(2014/07/07)
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- HETEROCYCLIC ALKYNYL BENZENE COMPOUNDS AND MEDICAL COMPOSITIONS AND USES THEREOF
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The heterocyclic alkynyl benzene compounds of formula (I), their pharmaceutically acceptable salts and stereoisomers thereof, as well as application in preparing drugs for preventing or treating tumors. The compounds can overcome the clinically induced resistance against Gleevec.
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Paragraph 0050; 0051
(2013/06/05)
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- HETEROCYCLIC ALKYNYL BENZENE COMPOUNDS AND MEDICAL COMPOSITIONS AND USES THEREOF
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The heterocyclic alkynyl benzene compounds of formula (I), their pharmaceutically acceptable salts and stereoisomers thereof, as well as application in preparing drugs for preventing or treating tumors. The compounds can overcome the clinically induced resistance against Gleevec.
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Paragraph 0125; 0129-0131
(2013/08/14)
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- Broad spectrum alkynyl inhibitors of T315I Bcr-Abl
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A series of alkyne-containing type II inhibitors with potent inhibitory activity of T315I Bcr-Abl has been identified. The most active compound 4 exhibits an EC50 of less than 1 nM against wild-type Bcr-Abl and an EC50 of 10 nM again
- Deng, Xianming,Lim, Sang Min,Zhang, Jianming,Gray, Nathanael S.
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scheme or table
p. 4196 - 4200
(2010/08/22)
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- Discovery of 3-[2-(imidazo[1,2- b ]pyridazin-3-yl)ethynyl]-4-methyl- N -{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant
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In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of Ile315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC 50s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABLT315I expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CML, including patients refractory to all currently approved therapies.
- Huang, Wei-Sheng,Metcalf, Chester A.,Sundaramoorthi, Raji,Wang, Yihan,Zou, Dong,Thomas, R. Mathew,Zhu, Xiaotian,Cai, Lisi,Wen, David,Liu, Shuangying,Romero, Jan,Qi, Jiwei,Chen, Ingrid,Banda, Geetha,Lentini, Scott P.,Das, Sasmita,Xu, Qihong,Keats, Jeff,Wang, Frank,Wardwell, Scott,Ning, Yaoyu,Snodgrass, Joseph T.,Broudy, Marc I.,Russian, Karin,Zhou, Tianjun,Commodore, Lois,Narasimhan, Narayana I.,Mohemmad, Qurish K.,Iuliucci, John,Rivera, Victor M.,Dalgarno, David C.,Sawyer, Tomi K.,Clackson, Tim,Shakespeare, William C.
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experimental part
p. 4701 - 4719
(2010/10/03)
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- AMIDES AS KINASE INHIBITORS
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The present invention is directed to amides, and pharmaceutical compositions thereof, which are inhibitors of kinases such as BCR AbI, FLT3, c-Kit, KDR, LCK, Epha2 and PDGFR subfamily and are useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways.
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Page/Page column 35; 36
(2010/09/17)
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- 9-(Arenethenyl)purines as dual Src/Abl kinase inhibitors targeting the inactive conformation: Design, synthesis, and biological evaluation
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A novel series of potent dual Src/Abl kinase inhibitors based on a 9-(arenethenyl)purine core has been identified. Unlike traditional dual Src/Abl inhibitors targeting the active enzyme conformation, these inhibitors bind to the inactive, DFG-out conformation of both kinases. Extensive SAR studies led to the discovery of potent and orally bioavailable inhibitors, some of which demonstrated in vivo efficacy. Once-daily oral administration of inhibitor 9i (AP24226) significantly prolonged the survival of mice injected intravenously with wild type Bcr-Abl expressing Ba/F3 cells at a dose of 10 mg/kg. In a separate model, oral administration of 9i to mice bearing subcutaneous xenografts of Src Y527F expressing NIH 3T3 cells elicited dose-dependent tumor shrinkage with complete tumor regression observed at the highest dose. Notably, several inhibitors (e.g., 14a, AP24163) exhibited modest cellular potency (IC50 = 300-400 nM) against the Bcr-Abl mutant T315I, a variant resistant to all currently marketed therapies for chronic myeloid leukemia. 2009 American Chemical Society.
- Huang, Wei-Sheng,Zhu, Xiaotian,Wang, Yihan,Azam, Mohammad,Wen, David,Sundaramoorthi, Raji,Thomas, R. Mathew,Liu, Shuangying,Banda, Geetha,Lentini, Scott P.,Das, Sasmita,Xu, Qihong,Keats, Jeff,Wang, Frank,Wardwell, Scott,Ning, Yaoyu,Snodgrass, Joseph T.,Broudy, Marc I.,Russian, Karin,Daley, George Q.,Iuliucci, John,Dalgarno, David C.,Clackson, Tim,Sawyer, Tomi K.,Shakespeare, William C.
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experimental part
p. 4743 - 4756
(2010/03/03)
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- p38α mitogen-activated protein kinase inhibitors: Optimization of a series of biphenylamides to give a molecule suitable for clinical progression
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p38α MAP kinase is a key anti-inflammatory target for rheumatoid arthritis, influencing biosynthesis of pro-inflammatory cytokines TNFα and IL-1β at a translational and transcriptional level. In this paper, we describe how we have optimized a series of no
- Aston, Nicola M.,Bamborough, Paul,Buckton, Jacqueline B.,Edwards, Christopher D.,Holmes, Duncan S.,Jones, Katherine L.,Patel, Vipulkumar K.,Smee, Penny A.,Somers, Donald O.,Vitulli, Giovanni,Walker, Ann L.
-
experimental part
p. 6257 - 6269
(2010/03/31)
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- Alkynylpyrimidine amide derivatives as potent, selective, and orally active inhibitors of Tie-2 kinase
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The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-F c conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation.
- Cee, Victor J.,Albrecht, Brian K.,Geuns-Meyer, Stephanie,Hughes, Paul,Bellon, Steve,Bready, James,Caenepeel, Sean,Chaffee, Stuart C.,Coxon, Angela,Emery, Maurice,Fretland, Jenne,Gallant, Paul,Gu, Yan,Hodous, Brian L.,Hoffman, Doug,Johnson, Rebecca E.,Kendall, Richard,Kim, Joseph L.,Long, Alexander M.,McGowan, David,Morrison, Michael,Olivieri, Philip R.,Patel, Vinod F.,Polverino, Anthony,Powers, David,Rose, Paul,Wang, Ling,Zhao, Huilin
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p. 627 - 640
(2007/10/03)
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- BICYCLIC HETEROARYL COMPOUNDS
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This invention relates to compounds of the general formula (I) in which the variable groups are as defined herein, and to their preparation and use.
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Page/Page column 51
(2008/06/13)
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- Aryl nitrogen-containing bicyclic compounds and methods of use
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The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including inflammation, cancer and related conditions. The compounds have a general Formula I wherein A1, As
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Page/Page column 36
(2010/11/26)
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- Synthesis and structure-activity relationships of a novel series of 2,3,5,6,7,9-hexahydrothieno[3,2-b]quinoline-8(4H)-one 1,1-dioxide K ATP channel openers: Discovery of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b] quinolin-8(4H)-one 1,1-dioxide (A-278637), a potent KATP opener that selectively inhibits spontaneous bladder contractions
-
Structure-activity relationships were investigated on a novel series of sulfonyldihydropyridine-containing KATP openers. Ring sizes, absolute stereochemistry, and aromatic substitution were evaluated for K ATP activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a select group of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of myogenic bladder overactivity, compound 14 and (-)-cromakalim 1 were found to inhibit spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than 1 in vivo and supports the concept that bladder-selective KATP channel openers may have utility in the treatment of overactive bladder.
- Carroll, William A.,Altenbach, Robert J.,Bai, Hao,Brioni, Jorge D.,Brune, Michael E.,Buckner, Steven A.,Cassidy, Christopher,Chen, Yiyuan,Coghlan, Michael J.,Daza, Anthony V.,Drizin, Irene,Fey, Thomas A.,Fitzgerald, Michael,Gopalakrishnan, Murali,Gregg, Robert J.,Henry, Rodger F.,Holladay, Mark W.,King, Linda L.,Kort, Michael E.,Kym, Philip R.,Milicic, Ivan,Tang, Rui,Turner, Sean C.,Whiteaker, Kristi L.,Yi, Lin,Zhang, Henry,Sullivan, James P.
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p. 3163 - 3179
(2007/10/03)
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- FUSED HETEROARYL DERIVATIVES FOR USE AS P38 KINASE INHIBITORS IN THE TREATMENT OF I.A. RHEUMATOID ARTHRISTIS
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Compounds of formula (I): wherein A is a 5-membered heteroaryl ring are inhibitors of p38 kinase and are useful in the treatment of conditions or disease states mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38, such as rheumatoid arthritis.
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Page/Page column 28
(2010/11/30)
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- HETEROARYL SUBSTITUTED BIPHENYL DERIVATIVES AS P38 KINASE INHIBITORS
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Compounds of formula (I) are inhibitors of p38 kinase and are useful in the treatment of conditions or disease states mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38.
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Page/Page column 19
(2010/02/07)
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- SUBSTITUTED THIAZOLE DERIVATIVES BEARING 3-PYRIDYL GROUPS, PROCESS FOR PREPARING THE SAME AND USE THEREOF
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The present invention provides a pharmaceutical composition having a steroid C17,20-lyase inhibitory activity, which is useful as a prophylactic or therapeutic agent of prostatism, tumor such as breast cancer and the like, more particularly, a steroid C17,20-lyase inhibitor containing a compound represented by the formula: wherein A1 is an aromatic hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, one of A2 and A3 is a hydrogen atom, a halogen atom, a C1-4 aliphatic hydrocarbon group optionally having substituents or an optionally esterified carboxyl group, the other of A2 and A3 is an aromatic hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, and at least one of A1, A2 and A3 is a 3-pyridyl group optionally having substituents, or a salt thereof or a prodrug thereof.
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Page/Page column 56
(2008/06/13)
-
- Substituted benzamide inhibitors of human rhinovirus 3C protease: Structure-based design, synthesis, and biological evaluation
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A series of nonpeptide benzamide-containing inhibitors of human rhinovirus (HRV) 3C protease was identified using structure-based design. The design, synthesis, and biological evaluation of these inhibitors are reported. A Michael acceptor was combined with a benzamide core mimicking the P1 recognition element of the natural 3CP substrate, α,β-Unsaturated cinnamate esters irreversibly inhibited the 3CP and displayed antiviral activity (EC50 0.60/μM, HRV-16 infected H1-HeLa cells). On the basis of cocrystal structure information, a library of substituted benzamide derivatives was prepared using parallel synthesis on solid support. A 1.9 A? cocrystal structure of a benzamide inhibitor in complex with the 3CP revealed a binding mode similar to that initially modeled wherein covalent attachment of the nucleophilic cysteine residue is observed. Unsaturated ketones displayed potent reversible inhibition but were inactive in the cellular antiviral assay and were found to react with nucleophilic thiols such as DTT.
- Reich, Siegfried H.,Johnson, Theodore,Wallace, Michael B.,Kephart, Susan E.,Fuhrman, Shella A.,Worland, Stephen T.,Matthews, David A.,Hendrickson, Thomas F.,Chan, Fora,Meador III, James,Ferre, Rose Ann,Brown, Edward L.,DeLisle, Dorothy M.,Patick, Amy K.,Binford, Susan L.,Ford, Clifford E.
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p. 1670 - 1683
(2007/10/03)
-
- Preparation and evaluation of some anti-arrhythmic and cardiac inotropic agents as 'cold' analogs of potential myocardial imaging agents
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The iodinated anti-arrhythmic analogs of disopyramide (1), procainamide (2) and lidocaine (3) and a new class of imidazolone cardiac inotropic phosphodiesterase inhibitors (4) and (5) (enoximone analogs), were prepared and tested as potential myocardial imaging agents. Compounds 1 and 2 were prepared by direct iodination using iodine monochloride in acetic acid, while 3-5 were prepared from suitable starting materials. The tissue load of the iodinated compounds was determined, in rats, on the basis of their iodine content using adaptation of a recent modification of Sandell and Kolthoff assay. The biodistribution of 125I-iodo derivatives of 2 and 4 were performed in mice. A pharmacokinetic study was performed using 5 to determine the optimal time of imaging post-injection. These compounds have shown significant localization in the heart tissue.
- El-Moselhy, Tarek F.,El-Kersh, Mohamed A.,Nyberg, Fred,Hede, Ragnar,Eldawy, Mohamed A.
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p. 163 - 170
(2007/10/03)
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- [125I]iodoproxyfan and related compounds: a reversible radioligand and novel classes of antagonists with high affinity and selectivity for the histamine H3 receptor.
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The synthesis and biological evaluation of new histamine H3 receptor antagonists with an iodinated aryl partial structure are described as part of an extensive research program to find model compounds for the development of a new radioligand with high H3 receptor affinity and specific activity. All compounds were tested for their H3 receptor antagonist activity in a [3H]-histamine-release assay with synaptosomes from rat cerebral cortex. The new leads with potent H3 receptor antagonist activity belong to a series of derivatives of 3-(1H-imidazol-4-yl)propanol with carbamate (4-7), ester (8-16), and ether (17-22) as functional groups. Structure-activity relationships are discussed. The most active compound in the functional test (-log Ki = 8.3) and in binding studies with [3H]-(R)-alpha-methylhistamine on rat cerebral cortex (-log Ki = 9.0) in vitro was 3-(1H-imidazol-4-yl)propyl (4-iodophenyl)methyl ether (iodoproxyfan, 19) exhibiting no central H3 receptor antagonist activity in vivo. The potency of iodoproxyfan is more than 300 times lower at H1, H2, alpha1, alpha2, beta1, 5-HT2A, 5-HT3, and M3 receptors than at histamine H3 receptors. Because of the high potency and selectivity of 19, this compound has also been prepared in the [125I]-iodinated form by a nucleophilic halogen exchange reaction using the corresponding bromo derivative 22 as a precursor. The newly prepared [125I]iodoproxyfan (23) possesses advantageous pharmacological properties and fulfills all criteria of a useful radioligand.
- Stark,Purand,Huels,Ligneau,Garbarg,Schwartz,Schunack
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p. 1220 - 1226
(2007/10/03)
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