Piotrowski DW.
*
et al.
Pfizer Worldwide Research & Development, Groton, USA
PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease.
J. Med. Chem. 2021;
64: 326-342
DOI:
10.1021/acs.jmedchem.0c01518
Key words
PF-07059013 - sickle cell anemia - biocatalysis - ketoreductase - Pfitzinger quinoline
synthesis - Mitsunobu reaction
Significance
Sickle cell disease is a common genetic disorder that affects 15 million people worldwide.
It is caused by a single point mutation on the β-chain of adult hemoglobin. PF-07059013
is a noncovalent modulator of hemoglobin that has entered phase I clinical trials
for the treatment of sickle cell disease.
Comment
Key steps in the synthesis depicted are (1) the asymmetric reduction of ketone E using the ketoreductase KRED101 from Codexis to afford enantiopure F in 94% yield (>99% ee), (2) the construction of quinoline I using a Pfitzinger reaction, and (3) a Mitsunobu reaction that links fragments F and K.
