Design, structure-activity relationships, X-ray crystal structure, and energetic contributions of a critical P1 pharmacophore: 3-Chloroindole-7-yl- based factor Xa inhibitors

Journal of Medicinal Chemistry

Volumn 51, Issue 23, 2008, Pages 7541-7551

  Shi, Yan ^a   Sitkoff, Doree ^a   Zhang, Jing ^a   Klei, Herbert E ^a   Kish, Kevin ^a   Liu, Eddie C K ^a   Hartl, Karen S ^a   Seiler, Steve M ^a   Chang, Ming ^a   Huang, Christine ^a   Youssef, Sonia ^a   Steinbacher, Thomas E ^a   Schumacher, William A ^a   Grazier, Nyeemah ^a   Pudzianowski, Andrew ^a   Apedo, Atsu ^a   Discenza, Lorell ^a   Yanchunas Jr , Joseph ^a   Stein, Philip D ^a   Atwal, Karnail S ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 (3 CHLORO 1H INDOL 7 YLAMINO) 2 CYANO N,N' DIMETHYL 3 [2 OXO 1 [2 OXO 2 (PYRROLIDIN 1 YL)ETHYL]AZEPAN 3 YLAMINO]ACRYLAMIDE; BLOOD CLOTTING FACTOR 10A INHIBITOR; GLYCINE; METHYL 3 (3 CHLORO 1H INDOL 7 YLAMINO) 2 CYANO 3 [2 OXO 1 [2 OXO 2 (PYRROLIDIN 1 YL)ETHYL]AZEPAN 3 YLAMINO]ACRYLATE; TYROSINE; UNCLASSIFIED DRUG;

ARTICLE; CRYSTAL STRUCTURE; DRUG DESIGN; HYDROGEN BOND; HYDROPHOBICITY; PHARMACOPHORE; PLASMA PROTEIN BINDING; STRUCTURE ACTIVITY RELATION;

ANIMALS; BINDING SITES; COMPUTER SIMULATION; CRYSTALLOGRAPHY, X-RAY; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DESIGN; ENZYME INHIBITORS; FACTOR XA; HUMANS; HYDROGEN BONDING; INDOLES; MICE; MODELS, CHEMICAL; MODELS, MOLECULAR; QUANTUM THEORY; STRUCTURE-ACTIVITY RELATIONSHIP; SURVIVAL ANALYSIS; VENOMS; VENOUS THROMBOSIS;

EID: 57349194524     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm800855x     Document Type: Article

References (80)

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49. Gly218 is sometimes referred to as Gly219 in the literature depending on how the FXa sequence was aligned with that of chymotripsinogen, on which the numbering system is based.
50. 11c several reports and crystal structures of a 2-linked-5-chloroindole P1 group that fills the base of the S1 pocket and hydrogen bonds to Gly218 carbonyl have appeared: Komoriya, S.; Haginoya, N.; Kobayashi, S.; Nagata, T.; Mochizuki, A.; Suzuki, M.; Yoshino, T.; Horino, H.; Nagahara, T.; Suzuki, M.; Isobe, Y.; Furugoori, T. Design, synthesis, and biological activity of non-basic compounds as factor Xa inhibitors: SAR study of S1 and aryl binding sites. Bioorg. Med 2005, 13, 3927-3954.
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65. Swiss Webster mice (24-38 g) were anesthetized with sodium pentobarbital (100 mg/kg, ip). Russell's viper venom (Sigma Chemical Co., St. Louis, MO) was prepared in 0.9% saline and injected into the tail vein at a dose of 7 μg/mouse in a volume of 0.1 mL given 15 min after induction of anesthesia. This dose of venom was found to be uniformly fatal in 105 mice with death occurring in an average of 1.5 ± 1.9 min (±SD, range was 1-12 min with 88% of mice dying within 2 min). Histological evaluation of several venom-treated mice revealed that early death was due to occlusion of pulmonary capillaries with fibrin aggregates, probably caused by initiation of blood coagulation by venom activation of factor X to factor Xa. A 5 mg/kg dose of test compounds or saline vehicle was administered by oral gavage 45 min before the venom injection. Survival was monitored out to 30 min after venom injection.
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67. Adler, M.; Davey, D. D.; Phillips, G. B.; Kim, S.-H.; Jancarik, J.; Rumennik, G.; Light, D. R.; Whitlow, M. Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa. Biochemistry 2000, 39, 12534-12542.
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