Discovery of the HCVNS3/4A protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II.: Key steps in structure-based optimization

被引：93

作者：

Prongay, Andrew J. ^{[1
]}

Guo, Zhuyan ^{[1
]}

Yao, Nanhua ^{[1
]}

Pichardo, John ^{[1
]}

Fischmann, Thierry ^{[1
]}

Strickland, Corey ^{[1
]}

Myers, Joseph, Jr. ^{[1
]}

Weber, Patricia C. ^{[1
]}

Beyer, Brian M. ^{[1
]}

Ingram, Richard ^{[1
]}

Hong, Zhi ^{[1
]}

Prosise, Winifred W. ^{[1
]}

Ramanathan, Lata ^{[1
]}

Taremi, S. Shane ^{[1
]}

Yarosh-Tomaine, Taisa ^{[1
]}

Zhang, Rumin ^{[1
]}

Senior, Mary ^{[1
]}

Yang, Rong-Sheng ^{[1
]}

Malcolm, Bruce ^{[1
]}

Arasappan, Ashok ^{[1
]}

Bennett, Frank ^{[1
]}

Bogen, Stephane L. ^{[1
]}

Chen, Kevin ^{[1
]}

Jao, Edwin ^{[1
]}

Liu, Yi-Tsung ^{[1
]}

Lovey, Raymond G. ^{[1
]}

Saksena, Anil K. ^{[1
]}

Venkatraman, Srikanth ^{[1
]}

Girijavallabhan, Viyyoor ^{[1
]}

Njoroge, F. George ^{[1
]}

Madison, Vincent ^{[1
]}

机构：

[1] Schering Plough Corp, Inst Res, Kenilworth, NJ 07033 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 10期

关键词：

D O I：

10.1021/jm060173k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine 139 to alanine (S139A) mutation were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets [the numbering of the subsites is as defined in Berger, A.; Schechter, I. Philos. Trans. R. Soc. London, Ser. B 1970, 257, 249-264]. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease that is currently in clinical trials.

引用

页码：2310 / 2318

页数：9

共 40 条

[21] (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1β and IL-18
Wannamaker, Woods
Davies, Robert
Namchuk, Mark
Pollard, John
Ford, Pamella
Ku, George
Decker, Caroline
Charifson, Paul
Weber, Peter
Germann, Ursula A.
Kuida, Keisuke
Randle, John C. R.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2007, 321 (02): : 509 - 516
[22] Evidence for the role of metabotropic glutamate (mGlu)2 not mGlu3 receptors in the preclinical antipsychotic pharmacology of the mGlu2/3 receptor agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039)
Fell, Matthew J.
Svensson, Kjell A.
Johnson, Bryan G.
Schoepp, Darryle D.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2008, 326 (01): : 209 - 217
[23] 2-{(E)-{{(R)-1-[(1R,5S,6R)-3,3-Dimethyl-2,4,7-trioxabicyclo[3.3.0]octan-6-yl]ethyl}imino}methyl}-6-{[(diphenylphosphino)oxy] phenyl}palladium(II) chloride
Guillarme, Stephane
Saluzzo, Christine
MOLBANK, 2024, 2024 (02)
[24] Structure-Based Drug Discovery of N-((R)-3-(7-Methyl-1H-indazol-5-yl)-1-oxo-1-(((S)-1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2′-oxo-1′,2′-dihydrospiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (HTL22562): A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine
Bucknell, Sarah J.
Ator, Mark A.
Brown, Alastair J. H.
Brown, Jason
Cansfield, Andrew D.
Cansfield, Julie E.
Christopher, John A.
Congreve, Miles
Cseke, Gabriella
Deflorian, Francesca
Jones, Christopher R.
Mason, Jonathan S.
O'Brien, M. Alistair
Ott, Gregory R.
Pickworth, Mark
Southall, Stacey M.
JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (14) : 7906 - 7920
[25] Experimental and Computational Chemistry studies on the inhibition of the Corrosion of Mild Steel in H2SO4 by (2s,5s,6r)-6-(2-(aminomethyl)-5-(3-(2-chlorophenyl)isoxazol-5-yl)benzamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
Eddy, Nnabuk O.
Ebenso, Eno E.
Ibok, Udo J.
Akpan, Emem E.
INTERNATIONAL JOURNAL OF ELECTROCHEMICAL SCIENCE, 2011, 6 (09): : 4296 - 4315
[26] INTERACTION BETWEEN NONCONJUGATED CHROMOPHORES .27. SYNTHESIS AND FORMATION OF IRONCARBONYL COMPLEXES OF 3',3'-DIMETHYL-2,3,5,6-TETRAMETHYLIDENESPIRO[BICYCLO[2.2.1]HEPTANE-7,2'-OXIRANE] - SINGLE-CRYSTAL AND MOLECULAR-STRUCTURE OF SYN,EXO2,3-ANTI,ENDO5,6-TRANS-MU-[(1R,2R,3S,4S,5S,6R)-C,2,3,C-ETA-C,5,6,C-ETA-(3',3'-DIMETHYL-2,3,5,6-TETRAMETHYLIDENESPIRO[BICYCLO[2.2.1]HEPTANE-7,2'-OXIRANE])BIS(TRICARBONYLIRON)3
RUBELLO, A
VOGEL, P
CHAPUIS, G
HELVETICA CHIMICA ACTA, 1987, 70 (06) : 1638 - 1648
[27] Crystal structure of ((1R)-1,2-((4S)-4-benzyl-2-oxo-oxazolidine-3-yl)-(1S)-1-methyl-2-oxo-ethoxy]-tert-butyl-amino-2,2-dimethyl-propyl)-phosphonic acid diethylester, C26H43N2O7P
Leroi, C
Ciufolini, MA
Perrin, M
Grosvallet, L
ZEITSCHRIFT FUR KRISTALLOGRAPHIE-NEW CRYSTAL STRUCTURES, 2003, 218 (01): : 39 - 40
[28] Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist:: In vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039)
Rorick-Kehn, Linda M.
Johnson, Bryan G.
Burkey, Jennifer L.
Wright, Rebecca A.
Calligaro, David O.
Marek, Gerard J.
Nisenbaum, Eric S.
Catlow, John T.
Kingston, Ann E.
Giera, Deborah D.
Herin, Marc F.
Monn, James A.
McKinzie, David L.
Schoepp, Darryle D.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2007, 321 (01): : 308 - 317
[29] Crystal structure of 1R,5S,8R,9S-8-azidomethyl-2-benzyl-6,6-dimethyl-3,7-dioxa-2-aza-bicyclo[3.3.1]nonan-9-ol,C16H22N4O3
Al-Harrasi, A
Brüdgam, I
Hartl, H
Reissig, HU
ZEITSCHRIFT FUR KRISTALLOGRAPHIE-NEW CRYSTAL STRUCTURES, 2005, 220 (04): : 599 - 600
[30] Five-membred 2,3-dioxoheterocycles: LXXXI. Reactions of 4,5-bis(methoxycarbonyl)-1H-pyrrole-2,3-diones with N-substituted 3-amino-5,5-dimethyl-2-cyclohex-2-en-1-ones. crystal and molecular structure of methyl 4′-hydroxy-6,6-dimethyl-1,1′-bis(4-methylphenyl)-2,4,5′-trioxo-1,1′,2,4,5,5′,6,7-octahydrospiro[indole-3,2′-pyrrole]-3′-carboxylate
P. S. Silaichev
M. A. Chudinova
P. A. Slepukhin
A. N. Maslivets
Russian Journal of Organic Chemistry, 2011, 47 : 1718 - 1722

← 1 2 3 4 →