Synthesis and structure-activity relationship of potent, selective and orally active anthranilamide-based factor Xa inhibitors

Application of weakly basic sulfoximine group as novel S4 binding element

Vrajesh Pandya, Mukul Jain, Ganes Chakrabarti, Hitesh Soni, Bhavesh Parmar, Balaji Chaugule, Jigar Patel, Tushar Jarag, Jignesh Joshi, Nirav Joshi, Akshyaya Rath, Vishal Unadkat, Bhavesh Sharma, Haresh Ajani, Jeevan Kumar, Kalapatapu V.V.M. Sairam, Harilal Patel, Pankaj Patel

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

A novel series of potent and efficacious factor Xa inhibitors which possesses sulfoximine moiety as novel S4 binding element in anthranilamide chemotype has been identified. Lead optimization at this novel P4 group led to many potent factor Xa inhibitors with excellent anticoagulant activity in human plasma. Selected compounds were dosed orally in rats and checked for their ex vivo prothrombin time prolonging activity, which resulted in identification of compound 5-chloro-N-(5-chloropyridin-2-yl)-2-(4-(N-(2-(diethylamino)acetyl)-S- methylsulfonimidoyl)benzamido)benzamide (18f). The detailed pharmacokinetic evaluation and subsequent metabolism study of 18f suggested the presence of an active metabolite. The compound 18f and its active metabolite 18b demonstrated excellent in vivo efficacy in both arterial and venous thrombosis model in rats and were found to be highly selective against related serine proteases. Based on this promising profile, compound 18f was selected for further evaluation.

Original languageEnglish (US)
Pages (from-to)136-152
Number of pages17
JournalEuropean Journal of Medicinal Chemistry
Volume58
DOIs
StatePublished - Dec 1 2012

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Structure-Activity Relationship
Metabolites
Rats
Plasma (human)
Pharmacokinetics
Prothrombin Time
Serine Proteases
Prothrombin
Metabolism
Human Activities
Venous Thrombosis
Anticoagulants
Factor Xa Inhibitors
anthranilamide
Lead
benzamide

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Synthesis and structure-activity relationship of potent, selective and orally active anthranilamide-based factor Xa inhibitors : Application of weakly basic sulfoximine group as novel S4 binding element. / Pandya, Vrajesh; Jain, Mukul; Chakrabarti, Ganes; Soni, Hitesh; Parmar, Bhavesh; Chaugule, Balaji; Patel, Jigar; Jarag, Tushar; Joshi, Jignesh; Joshi, Nirav; Rath, Akshyaya; Unadkat, Vishal; Sharma, Bhavesh; Ajani, Haresh; Kumar, Jeevan; Sairam, Kalapatapu V.V.M.; Patel, Harilal; Patel, Pankaj.

In: European Journal of Medicinal Chemistry, Vol. 58, 01.12.2012, p. 136-152.

Research output: Contribution to journalArticle

Pandya, V, Jain, M, Chakrabarti, G, Soni, H, Parmar, B, Chaugule, B, Patel, J, Jarag, T, Joshi, J, Joshi, N, Rath, A, Unadkat, V, Sharma, B, Ajani, H, Kumar, J, Sairam, KVVM, Patel, H & Patel, P 2012, 'Synthesis and structure-activity relationship of potent, selective and orally active anthranilamide-based factor Xa inhibitors: Application of weakly basic sulfoximine group as novel S4 binding element', European Journal of Medicinal Chemistry, vol. 58, pp. 136-152. https://doi.org/10.1016/j.ejmech.2012.10.005
Pandya, Vrajesh ; Jain, Mukul ; Chakrabarti, Ganes ; Soni, Hitesh ; Parmar, Bhavesh ; Chaugule, Balaji ; Patel, Jigar ; Jarag, Tushar ; Joshi, Jignesh ; Joshi, Nirav ; Rath, Akshyaya ; Unadkat, Vishal ; Sharma, Bhavesh ; Ajani, Haresh ; Kumar, Jeevan ; Sairam, Kalapatapu V.V.M. ; Patel, Harilal ; Patel, Pankaj. / Synthesis and structure-activity relationship of potent, selective and orally active anthranilamide-based factor Xa inhibitors : Application of weakly basic sulfoximine group as novel S4 binding element. In: European Journal of Medicinal Chemistry. 2012 ; Vol. 58. pp. 136-152.
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