Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors.: 5.: Potency, efficacy, and pharmacokinetic properties of modified C-3 side chain derivatives

被引：37

作者：

Sall, DJ ^{[1
]}

Bailey, DL ^{[1
]}

Bastian, JA ^{[1
]}

Buben, JA ^{[1
]}

Chirgadze, NY ^{[1
]}

Clemens-Smith, AC ^{[1
]}

Denney, ML ^{[1
]}

Fisher, MJ ^{[1
]}

Giera, DD ^{[1
]}

Gifford-Moore, DS ^{[1
]}

Harper, RW ^{[1
]}

Johnson, LM ^{[1
]}

Klimkowski, VJ ^{[1
]}

Kohn, TJ ^{[1
]}

Lin, HS ^{[1
]}

McCowan, JR ^{[1
]}

Palkowitz, AD ^{[1
]}

Richett, ME ^{[1
]}

Smith, GF ^{[1
]}

Snyder, DW ^{[1
]}

Takeuchi, K ^{[1
]}

Toth, JE ^{[1
]}

Zhang, MS ^{[1
]}

机构：

[1] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2000年 / 43卷 / 04期

关键词：

D O I：

10.1021/jm9903388

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit la led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead la. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS,-8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.

引用

页码：649 / 663

页数：15

共 11 条

[1] Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors.
Kohn, TJ
Takeuchi, K
Bailey, DL
Bastian, JA
Buben, JA
Clemens-Smith, AC
Denney, ML
Giera, DD
Gifford-Moore, DS
Harper, RW
Johnson, LM
Lin, HS
McCowan, JR
Richett, ME
Smith, GF
Sall, DJ
Snyder, DW
Toth, JE
Zhang, MS
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2000, 220 : U108 - U108
[2] Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors.: Part 6:: Further focus on the contracted C4′-side chain analogues
Takeuchi, K
Kohn, TJ
Harper, RW
Lin, HS
Gifford-Moore, DS
Richett, ME
Sall, DJ
Smith, GF
Zhang, MS
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (11) : 1199 - 1202
[3] Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors:: 3.: Enhancing activity by imposing conformational restriction in the C-4" side chain
Bastian, JA
Chirgadze, N
Denney, ML
Gifford-Moore, DS
Sall, DJ
Smith, GF
Wikel, JH
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1999, 9 (03) : 363 - 368
[4] The crystal structures of human α-thrombin complexed with active site-directed diamino benzo[b]thiophene derivatives:: A binding mode for a structurally novel class of inhibitors
Chirgadze, NY
Sall, DJ
Briggs, SL
Clawson, DK
Zhang, M
Smith, GF
Schevitz, RW
PROTEIN SCIENCE, 2000, 9 (01) : 29 - 36
[5] Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors:: 4.: SAR studies on the conformationally restricted C3-side chain of hydroxybenzo[b]thiophenes
Takeuchi, K
Kohn, TJ
Sall, DJ
Denney, ML
McCowan, JR
Smith, GF
Gifford-Moore, DS
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1999, 9 (05) : 759 - 764
[6] Dibasic benzo[b]thiophene derivatives as a novel class of thrombin inhibitors .3. Optimization of the C-3 sidechain.
Sall, DJ
Bastian, JA
Chirgadze, NY
Denney, ML
GiffordMoore, DS
Harper, TRW
Kohn, TJ
Lin, HS
McCowan, JR
Richett, ME
Smith, GF
Takeuchi, K
Zhang, M
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 1997, 214 : 59 - MEDI
[7] Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors:: 2.: Sidechain optimization and demonstration of in vivo efficacy
Zhang, MS
Bailey, DL
Bastian, JA
Briggs, SL
Chirgadze, NY
Clawson, DK
Denney, ML
Gifford-Moore, DS
Harper, RW
Johnson, LM
Klimkowski, VJ
Kohn, TJ
Lin, HS
McCowan, JR
Richett, ME
Sall, DJ
Smith, AJ
Smith, GF
Snyder, DW
Takeuchi, K
Utterback, BG
Yan, SCB
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1999, 9 (05) : 775 - 780
[8] Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors.: 2.: Exploring interactions at the proximal (S2) binding site.
Sall, DJ
Briggs, SL
Chirgadze, NY
Clawson, DK
Gifford-Moore, DS
Klimkowski, VJ
McCowan, JR
Smith, GF
Wikel, JH
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1998, 8 (18) : 2527 - 2532
[9] Dibasic benzo[b]thiophene derivatives as a novel class of active site-directed thrombin inhibitors .1. Determination of the serine protease selectivity, structure-activity relationships, and binding orientation
Sall, DJ
Bastian, JA
Briggs, SL
Buben, JA
Chirgadze, NY
Clawson, DK
Denney, ML
Giera, DD
GiffordMoore, DS
Harper, RW
Hauser, KL
Klimkowski, VJ
Kohn, TJ
Lin, HS
McCowan, JR
Palkowitz, AD
Smith, GF
Takeuchi, K
Thrasher, KJ
Tinsley, JM
Utterback, BG
Yan, SCB
Zhang, MS
JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (22) : 3489 - 3493
[10] Dibasic benzo[b]thiophene derivatives as a novel class of thrombin inhibitors .2. In vitro thrombin inhibition as a function of conformational effects and lipophilicity in the C-4' sidechain.
Sall, DJ
Bastian, JA
Denney, ML
GiffordMoore, DS
Harper, RW
Kohn, TJ
Lin, HS
Rampersaud, AA
Smith, GF
Takeuchi, K
Zhang, M
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 1997, 214 : 58 - MEDI

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