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Kamil Paruch,
Michael P. Dwyer,
Carmen Alvarez,
Courtney Brown,
Tin-Yau Chan,
Ronald J. Doll,
Kerry Keertikar,
Chad Knutson,
Brian McKittrick,
Jocelyn Rivera, [......],
Frances Shanahan,
Derek Wiswell,
Xiaoying Xu,
Quiao Zhou,
Ray A. James,
Vidyadhar M. Paradkar, Haengsoon Park,
Laura R. Rokosz,
Tara M. Stauffer,
Timothy J. Guzi
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ABSTRACT: Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.Keywords: Cyclin-dependent kinase; oncology therapeutics; SCH 727965
05/2010;
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Andrew G Cole,
Adolph C Bohnstedt,
Vidyadhar Paradkar,
Celia Kingsbury,
Jorge G Quintero, Haengsoon Park,
Yingchun Lu,
Ming You,
Irina Neagu,
David J Diller, [......],
Christopher M Riviello,
Koc-Kan Ho,
Tsung H Lin,
Bojing Wang,
Kenneth C Appell,
Matthew Sills,
Elizabeth Quadros,
Earl F Kimble,
Michael H J Ohlmeyer,
Maria L Webb
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ABSTRACT: A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-gamma (INF-gamma) production.
Bioorganic & medicinal chemistry letters 12/2009; 19(23):6788-92. · 2.65 Impact Factor
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Kamil Paruch,
Michael P Dwyer,
Carmen Alvarez,
Courtney Brown,
Tin-Yau Chan,
Ronald J Doll,
Kerry Keertikar,
Chad Knutson,
Brian McKittrick,
Jocelyn Rivera, [......],
Fran Shanahan,
Derek Wiswell,
Xiaoying Xu,
Quiao Zhou,
Ray A James,
Vidyadhar M Paradkar, Haengsoon Park,
Laura R Rokosz,
Tara M Stauffer,
Timothy J Guzi
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ABSTRACT: Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compound 15j is orally available and showed efficacy in a mouse A2780 xenograft model.
Bioorganic & Medicinal Chemistry Letters 12/2007; 17(22):6220-3. · 2.55 Impact Factor
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ABSTRACT: Synthetic investigations of ustiloxin natural products are described. The first total synthesis of ustiloxin F was completed in 15 steps via ethynyl aziridine ring-opening by a phenol derivative. The results of biological tests of synthetic ustiloxins D and F, and two analogs, O-Me-ustiloxin D and 6-Ile-ustiloxin, demonstrated that the free hydroxyl group ortho to the ether linkage is critical for activity and variations at the Val/Ala site produce changes in the biological activity suggesting the need for further perturbations at this site to more extensively study the tubulin binding.
Bioorganic & Medicinal Chemistry Letters 10/2006; 16(18):4804-7. · 2.55 Impact Factor
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ABSTRACT: Only a limited number of ligands have been successfully employed for the Ni-catalyzed asymmetric hydrovinylation reaction. Diarylphosphinites, carrying b-acylamino groups prepared from readily available carbohydrates, in conjunction with highly dissociated counteranions {[(3,5-(CF 3) 2 C 6 H 3 ] 4 B K or SbF 6 K }, effect the hydrovinylation of vinylarenes under ambient pressure of ethylene with high enantioselectivity. Nitrogen substituents such as –COCF 3 and COPh groups lead to isomerization of the primary products (3-arylbutenes) to Z-and E-2-aryl-2-butenes. In a prototypical synthesis of a 2-arylproionic acid, (S)-3-(4-bromophenyl)-1-butene (89% ee) has be transformed into (R)-ibuprofen by Ni-catalyzed cross-coupling with i-BuMgBr, followed by oxidation of the double bond with NaIO 4 and KMnO 4 . Asymmetric codimerization of norbonene and ethylene using binaphthol-derived phosphoramidites as ligands gives 1:1, 2:1 or polymeric adducts depending on the relative configurations and nature of the BINAP and amine moieties. With one of the phosphoramidite–Ni complexes, counteranions BAr 4 K [ArZ3,5-(CF 3) 2 C 6 H 3 ] and SbF 6 K , which had been used interchangeably in other reactions, give either a 1:1 adduct or a 2:1 adduct, respectively.
04/2005;
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ABSTRACT: Through a systematic examination of ligand and counterion effects, new protocols for a nearly quantitative and highly selective codimerization of ethylene and various functionalized vinylarenes have been discovered. In a typical reaction, 4-bromostyrene and ethylene undergo codimerization in the presence of 0.0035 equiv each of [(allyl)NiBr]2, triphenylphosphine, and AgOTf in CH2Cl2 at -56 degrees C to give 3-(4-bromophenyl)-1-butene in >98% yield and selectivity. Corresponding reactions with [(allyl)PdX]2 are much less efficient and less selective and may require further optimization before a viable system can be identified. Another useful protocol that gives comparable yield and selectivity involves the use of a single-component catalyst prepared from allyl 2-diphenylphosphinobenzoate, Ni(COD)2, and (C6F5)3B. Recognition of a synergistic relationship between a chiral hemilabile ligand (for example, (R)-2-methoxy-2'-diphenylphosphino-1,1'-binaphthyl, MOP) and a highly dissociated counteranion (BARF or SbF6) in an enantioselective version of the Ni-catalyzed reaction raises the prospects of developing a practical route for the synthesis of 3-arylbutenes. Several pharmaceutically relevant compounds, including widely used 2-arylpropionic acids, can be synthesized from these key intermediates. This reaction appears to be quite general. Synthesis of several new 2-diphenylphosphino-1,1-binaphthyl derivatives, prepared to probe the effect of hemilabile coordination on the efficiency and selectivity of the reaction, are also described.
The Journal of Organic Chemistry 10/2003; 68(22):8431-46. · 4.45 Impact Factor
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ABSTRACT: Only a limited number of ligands have been successfully employed for the Ni-catalyzed asymmetric hydrovinylation reaction. Diarylphosphonites prepared from readily available carbohydrates in conjunction with a highly dissociated counterion ([3,5-(CF3)2-C6H3)4B]- or SbF6-) effect the hydrovinylation of 4-bromostyrene or 4-isobutylstyrene under ambient pressure of ethylene with the best overall selectivities reported to date for these important substrates. In a prototypical synthesis of a 2-arylpropionic acid, 3-(4-bromophenyl)-1-butene (prepared in 98% isolated yield and 89% ee from 4-bromostyrene) has been transformed into (R)-ibuprofen by Ni-catalyzed cross-coupling with i-BuMgBr, ozonolysis, and subsequent oxidation of the resulting aldehyde.
Journal of the American Chemical Society 03/2002; 124(5):734-5. · 9.91 Impact Factor
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ABSTRACT: The total synthesis of ustiloxin D, a highly potent inhibitor of microtubule assembly, has been achieved. Notable features are the use of nucleophilic aromatic substitution (SNAr) for the construction of a chiral tertiary alkyl-aryl ether linkage, Sharpless asymmetric aminohydroxylation for the formation of the beta-hydroxytyrosine moiety, macrolactamization, and regioselective methylation.
Journal of the American Chemical Society 02/2002; 124(4):520-1. · 9.91 Impact Factor
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01/1998;
