Aroylguanidine-based factor Xa inhibitors: The discovery of BMS-344577
We report the design and synthesis of a novel class of N,N′-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure–activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC...
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Published in | Bioorganic & medicinal chemistry letters Vol. 19; no. 24; pp. 6882 - 6889 |
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Main Authors | , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Amsterdam
Elsevier Ltd
15.12.2009
Elsevier |
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Abstract | We report the design and synthesis of a novel class of N,N′-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure–activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC50=4nM, EC2×PT=7μM). However, the potent CYP3A4 inhibition activity (IC50=0.3μM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC50=9nM, EC2×PT=2.5μM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. |
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AbstractList | We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC sub(50) = 4 nM, EC sub(2xPT) = 7 mu M). However, the potent CYP3A4 inhibition activity (IC sub(50) = 0.3 mu M) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC sub(50) = 9 nM, EC sub(2xPT) = 2.5 mu M), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. We report the design and synthesis of a novel class of N,N′-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure–activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC50=4nM, EC2×PT=7μM). However, the potent CYP3A4 inhibition activity (IC50=0.3μM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC50=9nM, EC2×PT=2.5μM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4 nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity (IC(50)=0.3 microM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC(50)=9 nM, EC(2xPT)=2.5 microM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. |
Author | Atwal, Karnail S. Hartl, Karen S. Bisaha, Sharon N. Klei, Herbert E. Wang, Ying Shi, Yan Yanchunas, Joseph Kish, Kevin Li, Chi Zhang, Jing Shi, Mengxiao O’Connor, Stephen P. Stein, Philip D. Pudzianowski, Andrew T. Seiler, Steve M. Huang, Christine Steinbacher, Thomas E. Schumacher, William A. Sitkoff, Doree Liu, Eddie C.-K. |
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Keywords | CYP3A4 inhibition Orally active Factor Xa inhibitor Aroylguanidine Intravenous administration Isozyme Lactam Cardiovascular disease Coagulation Factor Xa Anticoagulant Acetylsalicylic acid Modeling Pyrrolidine derivatives Pyridine derivatives Vascular disease Structure activity relation Molecular model Antithrombotic agent Chemical synthesis Drug combination Unspecific monooxygenase Serine endopeptidases Enzyme Cytochrome P450 Oral administration Enzyme inhibitor Inhibitor enzyme complex In vitro Thrombosis Peptidases In vivo Chemotherapy Experimental disease Treatment Animal Hydrolases Carboxamide Drug-metabolizing enzyme Oxidoreductases Benzofuran derivatives Pharmacokinetics |
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Snippet | We report the design and synthesis of a novel class of N,N′-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors.... We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors.... |
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SubjectTerms | Anticoagulants - chemistry Anticoagulants - pharmacology Aroylguanidine Biological and medical sciences Blood. Blood coagulation. Reticuloendothelial system CYP3A4 inhibition Cytochrome P-450 CYP3A Cytochrome P-450 CYP3A Inhibitors Drug Discovery Factor Xa inhibitor Factor Xa Inhibitors Guanidines - chemistry Guanidines - pharmacology Humans Inhibitory Concentration 50 Medical sciences Orally active Pharmacology. Drug treatments Serine Proteinase Inhibitors - chemistry Serine Proteinase Inhibitors - pharmacology Structure-Activity Relationship |
Title | Aroylguanidine-based factor Xa inhibitors: The discovery of BMS-344577 |
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