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Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2.
- Source :
-
ACS medicinal chemistry letters [ACS Med Chem Lett] 2021 May 25; Vol. 12 (6), pp. 969-975. Date of Electronic Publication: 2021 May 25 (Print Publication: 2021). - Publication Year :
- 2021
-
Abstract
- To improve the metabolic stability profile of BMS-741672 ( 1a ), we undertook a structure-activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of 2d (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate 1a , the tert -butyl amine 2d showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability. Furthermore, compound 2d exhibited improved affinity for CCR5 and good activity in models of both monocyte migration and multiple sclerosis in the hCCR2 knock-in mouse. The synthesis of 2d was facilitated by the development of a simplified approach to key intermediate (4 R )- 9b that deployed a stereoselective reductive amination which may prove to be of general interest.<br />Competing Interests: The authors declare no competing financial interest.<br /> (© 2021 American Chemical Society.)
Details
- Language :
- English
- ISSN :
- 1948-5875
- Volume :
- 12
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- ACS medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 34141082
- Full Text :
- https://doi.org/10.1021/acsmedchemlett.1c00082