5T8E

Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part II: Optimization of 4-(pyrrolidin-1-yl)benzonitrile derivatives

Summary for 5T8E

• Entry DOI: 10.2210/pdb5t8e/pdb
• Related: 5T8J
• Descriptor: Androgen receptor, GLYCEROL, 2-chloro-4-[(2S,3S)-3-hydroxy-2-methylpyrrolidin-1-yl]-3-methylbenzonitrile, ... (4 entities in total)
• Functional Keywords: androgen receptor, selective androgen receptor modulators, sarms, hormone receptor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P10275
• Total number of polymer chains: 1
• Total formula weight: 30585.18

Authors

Wilson, K.P. (deposition date: 2016-09-07, release date: 2017-04-26)

Primary citation

Asano, M.,Hitaka, T.,Imada, T.,Yamada, M.,Morimoto, M.,Shinohara, H.,Hara, T.,Yamaoka, M.,Santou, T.,Nakayama, M.,Imai, Y.,Habuka, N.,Yano, J.,Wilson, K.,Fujita, H.,Hasuoka, A.
Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part II: Optimization of 4-(pyrrolidin-1-yl)benzonitrile derivatives.
Bioorg. Med. Chem. Lett., 27:1897-1901, 2017

PubMed Abstract: We recently reported a class of novel tissue-selective androgen receptor modulators (SARMs), represented by a naphthalene derivative A. However, their pharmacokinetic (PK) profiles were poor due to low metabolic stability. To improve the PK profiles, we modified the hydroxypyrrolidine and benzonitrile substituents of 4-(pyrrolidin-1-yl)benzonitrile derivative B, which had a comparable potency as that of compound A. This optimization led us to further modifications, which improved metabolic stability while maintaining potent androgen agonistic activity. Among the synthesized compounds, (2S,3S)-2,3-dimethyl-3-hydroxylpyrrolidine derivative 1c exhibited a suitable PK profile and improved metabolic stability. Compound 1c demonstrated significant efficacy in levator ani muscle without increasing the weight of the prostate in an in vivo study. In addition, compound 1c showed agonistic activity in the CNS, which was detected using sexual behavior induction assay.

PubMed: 28363748
DOI: 10.1016/j.bmcl.2017.03.038

Experimental method

X-RAY DIFFRACTION (2.71 Å)