title: Preclinical pharmacology of FL442, a novel nonsteroidal androgen receptor modulator.
abstract: The preclinical profiles of two most potent compounds of our recently published cycloalkane[d]isoxazole pharmacophore-based androgen receptor (AR) modulators, FL442 (4-(3a,4,5,6,7,7a-hexahydro-benzo[d]isoxazol-3-yl)-2-(trifluoromethyl)benzonitrile) and its nitro analog FL425 (3-(4-nitro-3-(trifluoromethyl)phenyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazole), were explored to evaluate their druggability for the treatment of AR dependent prostate cancer. The studies revealed that both compounds are selective to AR over other closely related steroid hormone receptors and that FL442 exhibits equal inhibition efficiency towards the androgen-responsive LNCaP prostate cancer cell line as the most widely used antiandrogen bicalutamide and the more recently discovered enzalutamide. Notably, FL442 maintains antiandrogenic activity with enzalutamide-activated AR mutant F876L. In contrast to bicalutamide, FL442 does not stimulate the VCaP prostate cancer cells which express elevated levels of the AR. Distribution analyses showed that [(14)CN]FL442 accumulates strongly in the mouse prostate. In spite of its low plasma concentration obtained by intraperitoneal administration, FL442 significantly inhibited LNCaP xenograft tumor growth. These findings provide a preclinical proof for FL442 as a promising AR targeted candidate for a further optimization.
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Pekka K
authors.initials: PK
authors.lastname: Poutiainen
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland; Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Tuulia
authors.initials: T
authors.lastname: Huhtala
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland; Institute of Dentistry, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Jääskeläinen
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland; Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, P.O. Box 5000, FI-90014, Finland.
authors.forename: Aleksanteri
authors.initials: A
authors.lastname: Petsalo
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Jenni
authors.initials: J
authors.lastname: Küblbeck
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Kaikkonen
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Jorma J
authors.initials: JJ
authors.lastname: Palvimo
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Hannu
authors.initials: H
authors.lastname: Raunio
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland; Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Ale
authors.initials: A
authors.lastname: Närvänen
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Peräkylä
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Risto O
authors.initials: RO
authors.lastname: Juvonen
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Paavo
authors.initials: P
authors.lastname: Honkakoski
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Reino
authors.initials: R
authors.lastname: Laatikainen
authors.affiliation: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland. Electronic address: juha.t.pulkkinen@uef.fi.
authors.forename: Juha T
authors.initials: JT
authors.lastname: Pulkkinen
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000494:pharmacology; D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009570:Nitriles / Q000493:pharmacokinetics / Q000494:pharmacology*; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011944:Receptors, Androgen / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D014105:Tosyl Compounds / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C000593238:3-(4-nitro-3-(trifluoromethyl)phenyl)-3a,4,5,6,7,7a-hexahydrobenzo(d)isoxazole; C000593237:4-(3a,4,5,6,7,7a-hexahydrobenzo(d)isoxazol-3-yl)-2-(trifluoromethyl)benzonitrile; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides; D000970:Antineoplastic Agents; D001549:Benzamides; D007555:Isoxazoles; D009570:Nitriles; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D014105:Tosyl Compounds; D010669:Phenylthiohydantoin; C540278:enzalutamide; C053541:bicalutamide
keywords: AR modulator; Androgen receptor; Antiandrogen; Prostate cancer