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Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577. | LitMetric

AI Article Synopsis

  • - A new class of N,N'-disubstituted aroylguanidine lactam derivatives was created, showing strong potential as oral FXa inhibitors, particularly the compound 22 which had a very low FXa IC(50)=4 nM but also had high CYP3A4 inhibition activity (IC(50)=0.3 microM).
  • - Research into the structure of compound 22 revealed that modifying the 6-position of the nicotinoyl group could reduce its negative CYP activity while maintaining its effectiveness as an FXa inhibitor.
  • - The efforts led to the identification of a new compound, 6-(dimethylcarbamoyl) nicotinoyl guanidine (BMS-344577),

Article 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 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.

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Source
http://dx.doi.org/10.1016/j.bmcl.2009.10.084DOI Listing

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