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2. Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility

Author

Rzasa, Robert M., Frohn, Michael J., Andrews, Kristin L., Chmait, Samer, Chen, Ning, Clarine, Jeffrey G., Davis, Carl, Eastwood, Heather A., Horne, Daniel B., Hu, Essa, Jones, Adrie D., Kaller, Matthew R., Kunz, Roxanne K., Miller, Silke, Monenschein, Holger, Nguyen, Thomas, Pickrell, Alexander J., Porter, Amy, Reichelt, Andreas, Zhao, Xiaoning, Treanor, James J.S., and Allen, Jennifer R.

Published
2014
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4. Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors

Author

Lanman, Brian A., primary, Allen, Jennifer R., additional, Allen, John G., additional, Amegadzie, Albert K., additional, Ashton, Kate S., additional, Booker, Shon K., additional, Chen, Jian Jeffrey, additional, Chen, Ning, additional, Frohn, Michael J., additional, Goodman, Guy, additional, Kopecky, David J., additional, Liu, Longbin, additional, Lopez, Patricia, additional, Low, Jonathan D., additional, Ma, Vu, additional, Minatti, Ana E., additional, Nguyen, Thomas T., additional, Nishimura, Nobuko, additional, Pickrell, Alexander J., additional, Reed, Anthony B., additional, Shin, Youngsook, additional, Siegmund, Aaron C., additional, Tamayo, Nuria A., additional, Tegley, Christopher M., additional, Walton, Mary C., additional, Wang, Hui-Ling, additional, Wurz, Ryan P., additional, Xue, May, additional, Yang, Kevin C., additional, Achanta, Pragathi, additional, Bartberger, Michael D., additional, Canon, Jude, additional, Hollis, L. Steven, additional, McCarter, John D., additional, Mohr, Christopher, additional, Rex, Karen, additional, Saiki, Anne Y., additional, San Miguel, Tisha, additional, Volak, Laurie P., additional, Wang, Kevin H., additional, Whittington, Douglas A., additional, Zech, Stephan G., additional, Lipford, J. Russell, additional, and Cee, Victor J., additional

Published
2019
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5. Highly regio- and enantioselective monoepoxidation of conjugated dienes

Author

Frohn, Michael, Dalkiewicz, Molly, Tu, Yong, Wang, Zhi-Xian, and Shi, Yian

Subjects
Epoxy compounds -- Research, Aromatic compounds -- Research, Ketones -- Usage, Enantiomers -- Research, Biological sciences, Chemistry
Abstract

A highly effective and mild asymmetric monoepoxidation technique for conjugated dienes with a fructose-derived chiral ketone as catalyst and Oxone as oxidant is presented. The regioselectivities and enantioselectivities are very high for most cases. The regioselectivity can be controlled in unsymmetrical dienes, through steric and electronic regulation. The olefin substrates include trans-disubstituted and trisubstituted olefins that can withstand a broad range of functional groups such as hydroxyl groups, TBS ethers or esters.

Published
1998

6. An efficient catalytic asymmetric epoxidation method

Author

Wang, Zhi-Xian, Tu, Yong, Frohn, Michael, Zhang, Jian-Rong, and Shi, Yian

Subjects
Epoxy compounds -- Research, Olefins -- Research, Chemistry
Abstract

Potassium peroxomonosulfate can be used as an oxidant and a fructose-derived ketone as a catalyst in an extremely effective catalytic asymmetric epoxidation method for olefins. It was found that pH is a vital factor for the expoxidation with dioxiranes generated in situ. In most cases, higher pH leads to quicker autodecomposition of potassium peroxomonosulfate, which in turn prompts a decrease in epoxidation efficiency. It is possible that the Baeyer-Villiger reaction is one of the key decomposition pathways for the catalyst.

Published
1997

8. Total syntheses of the assigned structures of lituarines B and C

Author

Smith, Amos B., III, Duffey, Matthew O., Basu, Kallol, Walsh, Shawn P., Suennemann, Hans W., and Frohn, Michael

Subjects
Biomolecules -- Chemical properties, Hydrogenation -- Analysis, Nuclear magnetic resonance -- Analysis, X-ray crystallography -- Technology application, Technology application, Chemistry
Abstract

The total syntheses of lituarine B and C are described. The X-ray crystallographic data has permitted the assignment of the structures of synthetic (+)-I[C.sub.50] = 5.5-7.5 nM and (+)-I[C.sub.50] = 1-3 nM.

Published
2008

9. Transition state studies on the dioxirane-mediated asymmetric epoxidation via kinetic resolution and desymmetrization

Author

Lorenz, Jon C., Frohn, Michael, Xiaoming, Zhou, Jian-Rong Zhang, Yian Shi, Yong Tang, and Burke, Christopher

Subjects
Olefins -- Chemical properties, Ethylene oxide -- Chemical properties, Biological sciences, Chemistry
Abstract

An efficient kinetic resolution process of trisubstituted cyclic olefins through a chiral dioxirane generated in situ from a fructose-derived ketone and Oxone is described. The substrates presented include a variety of 1,3-disubstituted and 1,6-disubstituted cyclohexenes with the stereogenic centers at allylic positions.

Published
2005

10. Discovery of a Covalent Inhibitor of KRASG12C(AMG 510) for the Treatment of Solid Tumors

Author

Lanman, Brian A., Allen, Jennifer R., Allen, John G., Amegadzie, Albert K., Ashton, Kate S., Booker, Shon K., Chen, Jian Jeffrey, Chen, Ning, Frohn, Michael J., Goodman, Guy, Kopecky, David J., Liu, Longbin, Lopez, Patricia, Low, Jonathan D., Ma, Vu, Minatti, Ana E., Nguyen, Thomas T., Nishimura, Nobuko, Pickrell, Alexander J., Reed, Anthony B., Shin, Youngsook, Siegmund, Aaron C., Tamayo, Nuria A., Tegley, Christopher M., Walton, Mary C., Wang, Hui-Ling, Wurz, Ryan P., Xue, May, Yang, Kevin C., Achanta, Pragathi, Bartberger, Michael D., Canon, Jude, Hollis, L. Steven, McCarter, John D., Mohr, Christopher, Rex, Karen, Saiki, Anne Y., San Miguel, Tisha, Volak, Laurie P., Wang, Kevin H., Whittington, Douglas A., Zech, Stephan G., Lipford, J. Russell, and Cee, Victor J.

Abstract

KRASG12Chas emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-“undruggable” target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRASG12Cto identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRASG12Cinhibitor currently in phase I clinical trials (NCT03600883).

Published
2020
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11. The optimization of aminooxadiazoles as orally active inhibitors of Cdc7

Author

Harrington, Paul E., Bourbeau, Matthew P., Fotsch, Christopher, Frohn, Michael, Pickrell, Alexander J., Reichelt, Andreas, Sham, Kelvin, Siegmund, Aaron C., Bailis, Julie M., Bush, Tammy, Escobar, Sonia, Hickman, Dean, Heller, Scott, Hsieh, Faye, Orf, Jessica N., Rong, Minqing, San Miguel, Tisha, Tan, Helming, Zalameda, Leeanne, and Allen, John G.

Published
2013
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12. Facile Modulation of Antibody Fucosylation with Small Molecule Fucostatin Inhibitors and Cocrystal Structure with GDP-Mannose 4,6-Dehydratase

Author

Allen, John G., primary, Mujacic, Mirna, additional, Frohn, Michael J., additional, Pickrell, Alex J., additional, Kodama, Paul, additional, Bagal, Dhanashri, additional, San Miguel, Tisha, additional, Sickmier, E. Allen, additional, Osgood, Steve, additional, Swietlow, Aleksander, additional, Li, Vivian, additional, Jordan, John B., additional, Kim, Ki-Won, additional, Rousseau, Anne-Marie C., additional, Kim, Yong-Jae, additional, Caille, Seb, additional, Achmatowicz, Mike, additional, Thiel, Oliver, additional, Fotsch, Christopher H., additional, Reddy, Pranhitha, additional, and McCarter, John D., additional

Published
2016
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13. Quinolinone-based agonists of S1P1: Use of a N-scan SAR strategy to optimize in vitro and in vivo activity

Author

Pennington, Lewis D., Croghan, Michael D., Sham, Kelvin K.C., Pickrell, Alexander J., Harrington, Paul E., Frohn, Michael J., Lanman, Brian A., Reed, Anthony B., Lee, Matthew R., Xu, Han, McElvain, Michele, Xu, Yang, Zhang, Xuxia, Fiorino, Michael, Horner, Michelle, Morrison, Henry G., Arnett, Heather A., Fotsch, Christopher, Tasker, Andrew S., Wong, Min, and Cee, Victor J.

Published
2012
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14. Kinetic resolution of racemic cyclic olefins via chiral dioxirane

Author

Frohn, Michael, Zhou, Xiaoming, Zhang, Jian-Rong, Tang, Yong, and Zhi, Yian

Subjects
Cyclic compounds -- Research, Olefins -- Research, Chemistry
Abstract

Research was conducted to demonstrate that the kinetic resolution of 1,3- and 1,6-disubstituted cyclohexanes through chiral dioxirane is possible. High-resolution efficiency was obtained for a number of trisubstituted cyclic olefin substrates, which offers a valuable method for preparing certain chiral intermediates in a straightforward fashion. Since the dioxirane-mediated resolution is expected to depend largely on steric interactions, this process may be used on olefins with a variety of substituents.

Published
1999

15. A dramatic pH effect leads to a catalytic asymmetric epoxidation

Author

Wang, Zhi-Xian, Tu, Yong, Frohn, Michael, and Shi, Yian

Subjects
Epoxy compounds -- Analysis, Ketones -- Analysis, Chemical tests and reagents -- Analysis, Hydrogen-ion concentration -- Analysis, Biological sciences, Chemistry
Abstract

The kinetic parameters that mediate the epoxidation efficiency of a fructose-derived ketone catalyst were analyzed during the catalytic asymmetric epoxidation of trans-B-methylstyrene. The catalytic asymmetric epoxidation process was dependent on hydrogen-ion concentration (pH) such that the efficiency of the reaction was reduced by elevated pH due to the rapid autodecomposition of Oxone. Furthermore, an increase in pH levels attenuated the competing Baeyer-Villiger reaction.

Published
1997

16. Abstract 711: Small molecule compounds that target cell division cycle 7 (Cdc7) kinase inhibit cell proliferation and tumor growth.

Author

Bailis, Julie, primary, Fang, Li, additional, Orf, Jessica, additional, Heller, Scott, additional, Bush, Tammy, additional, Bourbeau, Matthew, additional, Escobar, Sonia, additional, Frohn, Michael, additional, Harrington, Paul, additional, Hsieh, Faye, additional, Pickrell, Alexander, additional, Sham, Kelvin, additional, Siegmund, Aaron, additional, Tan, Helming, additional, Zalameda, Leeanne, additional, Allen, John, additional, and Wickramasinghe, Dineli, additional

Published
2013
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18. 4-Methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide: A Potent and Selective Agonist of S1P1

Author

Pennington, Lewis D., primary, Sham, Kelvin K. C., additional, Pickrell, Alexander J., additional, Harrington, Paul E., additional, Frohn, Michael J., additional, Lanman, Brian A., additional, Reed, Anthony B., additional, Croghan, Michael D., additional, Lee, Matthew R., additional, Xu, Han, additional, McElvain, Michele, additional, Xu, Yang, additional, Zhang, Xuxia, additional, Fiorino, Michael, additional, Horner, Michelle, additional, Morrison, Henry G., additional, Arnett, Heather A., additional, Fotsch, Christopher, additional, Wong, Min, additional, and Cee, Victor J., additional

Published
2011
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31. Structural probing of ketone catalysts for asymmetric epoxidation

Author

Tu, Yong, Wang, Zhi-Xian, Frohn, Michael, He, Mingqi, Yu, Hongwu, Tang, Yong, and Shi, Yian

Subjects
Ketones -- Usage, Catalysts -- Research, Epoxy compounds -- Research, Olefins -- Research, Biological sciences, Chemistry
Abstract

The use of carbohydrate-derived chiral ketones as asymmetric epoxidation catalysts was investigated. Results reveal that ketones derived from fructose are effective catalysts. The structural requirements for these catalysts are very strict and different olefins may require structurally different ketone catalysts. The epoxidation reaction is probed in order to gain an understanding of the requirements for the development of new ketone catalysts.

Published
1998

37. Quinolinone-based agonists of S1P1: Use of a N-scan SAR strategy to optimize in vitro and in vivo activity

Author

Pennington, Lewis D., Croghan, Michael D., Sham, Kelvin K.C., Pickrell, Alexander J., Harrington, Paul E., Frohn, Michael J., Lanman, Brian A., Reed, Anthony B., Lee, Matthew R., Xu, Han, McElvain, Michele, Xu, Yang, Zhang, Xuxia, Fiorino, Michael, Horner, Michelle, Morrison, Henry G., Arnett, Heather A., Fotsch, Christopher, Tasker, Andrew S., and Wong, Min

Subjects
*QUINOLONE antibacterial agents, *DRUG development, *PHARMACOKINETICS, *PHARMACODYNAMICS, *DRUG design, *PHARMACEUTICAL chemistry
Abstract

Abstract: We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P1 agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P1 RI; 17: EC50 =0.020μM, 120% efficacy; 5: EC50 =0.070μM, 110% efficacy) and selectivity (hS1P3 Ca2+ flux; 17: EC50 >25μM; 5: EC50 =1.5μM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15L/h/kg, V dss =5.1L/kg, T 1/2 =24h, %F =110; 5: CL=0.93L/h/kg, V dss =11L/kg, T 1/2 =15h, %F =60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=−67%; 5: 3mg/kg po, 24h PLC POC=−51%) in rat. [Copyright &y& Elsevier]

Published
2012
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38. Discovery of a Covalent Inhibitor of KRAS G12C (AMG 510) for the Treatment of Solid Tumors.

Author

Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK, Chen JJ, Chen N, Frohn MJ, Goodman G, Kopecky DJ, Liu L, Lopez P, Low JD, Ma V, Minatti AE, Nguyen TT, Nishimura N, Pickrell AJ, Reed AB, Shin Y, Siegmund AC, Tamayo NA, Tegley CM, Walton MC, Wang HL, Wurz RP, Xue M, Yang KC, Achanta P, Bartberger MD, Canon J, Hollis LS, McCarter JD, Mohr C, Rex K, Saiki AY, San Miguel T, Volak LP, Wang KH, Whittington DA, Zech SG, Lipford JR, and Cee VJ

Subjects
Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Clinical Trials as Topic, Dogs, Drug Discovery, Humans, Isomerism, Madin Darby Canine Kidney Cells, Mice, Inbred BALB C, Mice, Nude, Mutation, Piperazines chemistry, Piperazines pharmacology, Proto-Oncogene Proteins p21(ras) genetics, Pyridines chemistry, Pyridines pharmacokinetics, Pyridines pharmacology, Pyrimidines chemistry, Pyrimidines pharmacology, Pyrimidinones chemistry, Pyrimidinones pharmacokinetics, Rats, Structure-Activity Relationship, Antineoplastic Agents therapeutic use, Neoplasms drug therapy, Piperazines therapeutic use, Proto-Oncogene Proteins p21(ras) antagonists & inhibitors, Pyridines therapeutic use, Pyrimidines therapeutic use, Pyrimidinones therapeutic use
Abstract

KRAS G12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRAS G12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRAS G12C inhibitor currently in phase I clinical trials (NCT03600883).

Published
2020
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39. Diversity-oriented synthesis of polyketide natural products via iterative chemo- and stereoselective functionalization of polyenoates: development of a unified approach for the C(1-19) segments of lituarines A-C.

Author

Smith AB 3rd, Walsh SP, Frohn M, and Duffey MO

Subjects
Stereoisomerism, Biological Products chemical synthesis, Epoxy Compounds chemistry, Spiro Compounds chemistry
Abstract

A unified, stereocontrolled synthesis of the C(1-19) segments of the lituarines A-C (1-3) has been achieved, highlighted by application of an iterative chemo- and stereoselective trienoate functionalization protocol, a strategy that holds considerable promise for the diversity oriented synthesis of polyketides.

Published
2005
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