5V8Q

Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs): Part III

Summary for 5V8Q

• Entry DOI: 10.2210/pdb5v8q/pdb
• Descriptor: Androgen receptor, GLYCEROL, 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile, ... (4 entities in total)
• Functional Keywords: androgen receptor, selective androgen receptor modulators, sarms, signaling protein
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P10275
• Total number of polymer chains: 1
• Total formula weight: 29562.51

Authors

Wilson, K.P. (deposition date: 2017-03-22, release date: 2017-05-24, Last modification date: 2024-10-30)

Primary citation

Aikawa, K.,Asano, M.,Ono, K.,Habuka, N.,Yano, J.,Wilson, K.,Fujita, H.,Kandori, H.,Hara, T.,Morimoto, M.,Santou, T.,Yamaoka, M.,Nakayama, M.,Hasuoka, A.
Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs) Part III: Discovery of 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2f as a clinical candidate.
Bioorg. Med. Chem., 25:3330-3349, 2017

PubMed Abstract: We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring. As a consequence, we found that 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (2f) had ideal SARM profiles in Hershberger assay and sexual behavior induction assay. Furthermore, 2f showed good pharmacokinetic profiles in rats, dogs, monkeys, excellent nuclear selectivity and acceptable toxicological profiles. We also determined its binding mode by obtaining the co-crystal structures with AR.

PubMed: 28454849
DOI: 10.1016/j.bmc.2017.04.018

Experimental method

X-RAY DIFFRACTION (1.44 Å)