- Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity
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Poly(adenosine 5′-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity of PARP proteins. Optimization of our lead compound 1 ((Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC50 = 434 nM) led to a tetrazolyl analogue (51, IC50 = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC50 = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC50 values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC50 values comparable to clinical inhibitors. X-ray crystal structures of the key inhibitors bound to PARP-1 illustrated the mode of interaction with analogue appendages extending toward the PARP-1 adenosine-binding pocket. Compound 81, an isoform-selective PARP-1/-2 (IC50 = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast cancer gene 1 (BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.
- Velagapudi, Uday Kiran,Langelier, Marie-France,Delgado-Martin, Cristina,Diolaiti, Morgan E.,Bakker, Sietske,Ashworth, Alan,Patel, Bhargav A.,Shao, Xuwei,Pascal, John M.,Talele, Tanaji T.
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p. 5330 - 5357
(2019/06/07)
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- An Environmentally Friendly Method for N-Methylation of 5-Substituted 1H-Tetrazoles with a Green Methylating Reagent: Dimethyl Carbonate
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An environmentally friendly method was established for the N-methylation of the 5-substituted 1H-tetrazoles with a green reagent: DMC. DABCO was the optimal catalyst, and hazardous chemicals were avoided in this protocol. A plausible catalytic mechanism is proposed, which consists of a DABCO-activated process and a thermally induced rearrangement of tetrazole carbamates.
- Xie, Aming,Zhang, Qiang,Liu, Yangyang,Feng, Liandong,Hu, Xinyu,Dong, Wei
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p. 1483 - 1487
(2015/10/06)
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- THIAZALOPYRROLIDINE INHIBITORS OF ROR-GAMMA
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Provided are novel compounds of Formula (I): pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of diseases and disorders mediated by ROR?. Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I) and methods for their use in treating one or more inflammatory, metabolic, autoimmune and other diseases or disorders.
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Paragraph 00155; 00181
(2014/11/13)
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- Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: Potent inhibitors of R5 HIV-1 replication
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The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
- Skerlj, Renato,Bridger, Gary,Zhou, Yuanxi,Bourque, Elyse,McEachern, Ernest,Metz, Markus,Harwig, Curtis,Li, Tong-Shuang,Yang, Wen,Bogucki, David,Zhu, Yongbao,Langille, Jonathan,Veale, Duane,Ba, Tuya,Bey, Michael,Baird, Ian,Kaller, Alan,Krumpak, Maria,Leitch, David,Satori, Michael,Vocadlo, Krystyna,Guay, Danielle,Nan, Susan,Yee, Helen,Crawford, Jason,Chen, Gang,Wilson, Trevor,Carpenter, Bryon,Gauthier, David,MacFarland, Ron,Mosi, Renee,Bodart, Veronique,Wong, Rebecca,Fricker, Simon,Schols, Dominique
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supporting information
p. 8049 - 8065
(2013/11/06)
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- Pyrimidine derivatives and processes for the preparation thereof
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4-Amino-1H-pyrazolo[3,4-d]pyrimidine derivatives of formula I wherein the substituents are as defined in claim 1, are described.These compounds inhibit the tyrosine kinase activity of the receptor for epidermal growth factor (EGF) and c-erbB2 kinase and can be used as anti-tumor agents.
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- Insecticidal N-(substituted arylmethyl)-4-[bis(substituted phenyl or pyridyl)methyl]piperidines
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Compounds of the following structure, the corresponding N-oxides and agriculturally acceptable salts thereof, are disclosed as effective insecticides: whereinU is —(CH2)n—;Q is hydroxy; andR is: and whereinV, W, Y, and Z are each hydrogen;X is a five- or six-membered heterocycle; optionally substituted with bromine, chlorine, fluorine, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, or aminocarbonyl; and the heterocycle is optionally connected to the phenyl ring through a —O—, —S—, —(CH2)p, —C(O)—, or —O—(CR3R4)q linkage;R1 and R2 are independently selected from phenyl or pyridyl substituted with pentahalothio, haloalkylthio, haloalkylsulfinyl, or haloalkylsulfonyl; phenyl substituted with —OC(M)2O—, where M is bromine, chorine or fluorine, to provide a dihalobenzodioxolyl fused ring; or pyridyl substituted with —OC(M)2O— to provide a dihalodioxolenopyridyl fused ring;R3 and R4 are independently selected from hydrogen and methyl;n and p are independently 1, 2, or 3; andq is 1 or 2; with the proviso that at least one of R1 and R2 is substituted in the para position of the phenyl ring or the 5-position of the 2-pyridyl ring; each alkyl portion of said optional substituent on X wherein the optional substituent is alkyl, haloalkyl, alkoxyl, haloalkoxyl, alkoxyalkyl, or haloalkoxyalkyl contains from 1 to 4 carbon atoms; each heterocycle contains from 1 to 4 nitrogen atoms, 1 or 2 oxygen or sulfur atoms, or 1 or 2 nitrogen atoms and an oxygen or sulfur atom; and the corresponding N-oxides and agriculturally acceptable salts.
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- New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: Candidates for clinical development
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On the basis of previously described X-ray studies of an enzyme/aza- dipeptide complex, aza-dipeptide analogues carrying N-(bis-aryl-methyl) substituents on the (hydroxethyl)hydrazine moiety have been designed and synthesized as HIV-1 protease inhibitors. By using either equally (12) or orthogonally (13) protected dipeptide isosteres, symmetrically and asymmetrically acylated aza-dipeptides can be synthesized. This approach led to the discovery of very potent inhibitors with antiviral activities (ED50) in the subnanomolar range. Acylation of the (hydroxethyl)hydrazine dipeptide isostere with the L-tert-leucine derivative 29 increased the oral bioavailability significantly when compared to the corresponding L-valine or L-isoleucine derivatives. The bis (L-tert-leucine) derivatives CGP 75355, CGP 73547, CGP 75136, and CGP 75176 combine excellent antiviral activity with high blood concentration after oral administration. Furthermore, they show no cross-resistance with saquinavir-resistant strains and maintain activity against indinavir-resistant ones. Consequently they qualify for further profiling as potential clinical candidates.
- Bold, Guido,F?ssler, Alexander,Capraro, Hans-Georg,Cozens, Robert,Klimkait, Thomas,Lazdins, Janis,Mestan, Jürgen,Poncioni, Bernard,R?sel, Johannes,Stover, David,Tintelnot-Blomley, Marina,Acemoglu, Figan,Beck, Werner,Boss, Eugen,Eschbach, Martin,Hürlimann, Thomas,Masso, Elvira,Roussel, Serge,Ucci-Stoll, Katharina,Wyss, Dominique,Lang, Marc
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p. 3387 - 3401
(2007/10/03)
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- Insecticidal N-(substituted arylmethyl)-4-[bis(substituted phenyl)methyl]piperidines
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Compounds of the following structure, the corresponding N-oxides and agriculturally acceptable salts, are disclosed as effective insecticides: STR1 in which U is selected from --(CH2)n -- and ethylidene; Q is selected from hydrogen, hydroxy, sulfhydryl, and fluorine; R is STR2 in which V is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsilyloxy, dialkylamino, cyano, nitro, hydroxy, and phenyl; Y and Z are independently selected from hydrogen and alkoxy; W and X taken together is --OCH2 CH2 O--, --CH2 C(CH3)2 O--, --OC(CH3)2 O--, or --N=C(C2 H5)O--; R1 and R2 are independently selected from phenyl substituted with halogen, alkyl, haloalkyl, haloalkoxy, alkoxyalkyl, hydroxy, arylthio, alkoxy, dialkylamino, dialkylaminosulfonyl, hydroxyalkylaminocarbonyl, alkylsulfonyloxy, and haloalkylsulfonyloxy; and n is 1, 2, or 3.
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- Insecticidal n-(substituted arylmethyl)-4-[bis(substituted phenyl) methyl]pi
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Compounds of the following structure, the corresponding N-oxides and agriculturally acceptable salts, are disclosed as effective insecticides: STR1 in which U is selected from STR2 Q is selected from hydrogen, hydroxy, sulfhydryl, and fluorine; R is selected from a heterocycle having 5 or 6 ring atoms, optionally fused to a benzene ring, and STR3 wherein V, W, X, Y, Z are as defined in the specification.
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