Unveiling the Science behind Apixaban: A Remarkable Drug Discovery Case Study. Delve into the captivating journey of uncovering Apixaban, a groundbreaking anticoagulant. This compelling case study showcases the intricate process of drug discovery, from target identification to clinical trials. Gain valuable insights into the key factors contributing to the success of Apixaban, including molecular design, mechanism of action, and therapeutic potential. Explore the transformative impact of this discovery in the field of cardiovascular medicine. Key takeaways: molecular design strategies, therapeutic efficacy, and future prospects in anticoagulant therapy.

1. Apixaban, Selective
Inhibitor of Factor Xa

2. History from Thrombosis to Warfarin
Warfarin competitively inhibits
the vitamin K, Through this
mechanism, warfarin can
deplete functional vitamin K
reserves and thereby reduce the
synthesis of active clotting
factors.
Thrombosis is blood clots
blocking veins or arteries
which leads to Cardiovascular
problems and even heart
attack.

3. What is Factor Xa?
The best drug target for antithrombotic activity
Factor Xa is a serine protease which cleaves prothrombin to
generate thrombin and lies at the crossroads of the extrinsic and
intrinsic coagulation pathway. Only a small amount of factor Xa is
needed to generate many molecules of thrombin

4. Structure based
Drug Discovery
01

5. Active site Analysis
Active sites S1 & S4
S1 is an carbonyl amide of
serine labelled as G216
S4 is a lipophilic site prefers
basic groups with pi stacking
labelled as D189
With library data and HTS
benzamidine moiety was
suggested for S4 pocket

6. They started with the bis-
benzamidines
It was clearly not a clever decision, after further advances they
discovered about the isoxaziline derivatives by studying the
GPIIa/IIIb antagonists which were known and relatively inhibits
FXa too.
After further screening through the library, they got leads which
showed 30 folds improvements.

7. Driving the
affinity
02

8. Combinations tried to increase the
affinity of the molecule for the targets
To check for the increasing affinity
they quantified the binding energy.

9. Glide Score and Ki
Glide Score
Basically it is binding energy
Inhibition constant (Ki)
Rate constant of inhibition lower the
constant lower is the binding energy
Isoxazolines Pyrazole Fluorines
Combinations and bioisosteres

10. Affinity increases with “>>”
SAR of The molecule

11. They came across many drugs which had
higher affinity but poor oral bioavailibility
so they changed some subgroups to
improve so.
You obviously didn’t know fact:
Razaxaban was the first FXa inhibitor which passed the preclinical test and
phased off in second clinical trials.

12. Structural diversity
Now the skeleton is finalized but its not that rigid due to the free
amide in between, the scaffold is developed to Pyrimidinone group
and then a Lactum. The aryl sulfonamide is changed with methyl for
improving bioavailability and half life.
Pyrimidinone
Delta- Lactam

13. Apixaban
• Putted back the methoxyphenol which had
the highest affinity for S1 pocket.
• Replaced the earlier nonbasic SO2Me2 with
a basic amide and then rigidification turns it
into a lactam for the S4 pocket.
Glide Score: -114.67 kcal/mol
Ki: 0.08nM

14. Binding of Apixaban on FactorXa

15. Bioisosteres (technically not)
The P4 and P1 sites are modified according to
previuos SAR profile.
Apixaban Rivaroxaban

16. Metabolism

17. Phewww!
Its Over