ABSTRACT
Modification on a lead series of [1,4]oxazino[3,2-g]quinolin-7-ones at the 2-position led to selective androgen receptor modulators with improved in vivo activity. The most potent analog (-)-33a exhibited full maintenance of levator ani muscle at 3mg/kg and reduced activity on ventral prostate weight in a 2-week orally-dosed and orchidectomized rat maintenance assay.
Subject(s)
Anabolic Agents/pharmacology , Oxazines/pharmacology , Prostate/drug effects , Quinolones/pharmacology , Receptors, Androgen , Administration, Oral , Anabolic Agents/chemical synthesis , Androgen Receptor Antagonists , Androgens , Animals , Male , Models, Chemical , Orchiectomy , Organ Size/drug effects , Oxazines/chemical synthesis , Prostate/anatomy & histology , Quinolones/chemical synthesis , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Testosterone/pharmacologyABSTRACT
The androgen receptor is a ligand inducible transcription factor that is involved in a broad range of physiological functions. Here we describe the discovery of a new class of orally available selective androgen receptor modulators. The lead compound, 6-[(2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-4-trifluoromethylquinolin-2(1H)-one (6a), showed excellent anabolic activity in muscle with reduced effect on the prostate in a rat model of hypogonadism. The compound also improved bone strength in a rat model of post-menopausal osteoporosis.
Subject(s)
Anabolic Agents/chemical synthesis , Androgen Receptor Antagonists , Androgens , Bone Density Conservation Agents/chemical synthesis , Pyrrolidines/chemical synthesis , Quinolines/chemical synthesis , Quinolones/chemical synthesis , Administration, Oral , Anabolic Agents/pharmacokinetics , Anabolic Agents/pharmacology , Animals , Biological Availability , Bone Density Conservation Agents/pharmacokinetics , Bone Density Conservation Agents/pharmacology , Female , Humans , Hypogonadism/drug therapy , Hypogonadism/pathology , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Organ Size/drug effects , Osteoporosis, Postmenopausal/drug therapy , Prostate/drug effects , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Quinolines/pharmacokinetics , Quinolines/pharmacology , Quinolones/pharmacokinetics , Quinolones/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Recent interest in orally available androgens has fueled the search for new androgens for use in hormone replacement therapy and as anabolic agents. In pursuit of this, we have discovered a series of novel androgen receptor modulators derived from 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. These compounds were synthesized and evaluated in competitive binding assays and an androgen receptor transcriptional activation assay. A number of compounds from the series demonstrated single-digit nanomolar agonist activity in vitro. In addition, lead compound (R)-16e was orally active in established rodent models that measure androgenic and anabolic properties of these agents. In this assay, (R)-16e demonstrated full efficacy in muscle and only partially stimulated the prostate at 100 mg/kg. These data suggest that these compounds may be utilized as selective androgen receptor modulators or SARMs. This series represents a novel class of compounds for use in androgen replacement therapy.
Subject(s)
Oxazines/chemical synthesis , Quinolones/chemical synthesis , Receptors, Androgen/drug effects , Anabolic Agents/chemical synthesis , Anabolic Agents/chemistry , Anabolic Agents/pharmacology , Androgens , Animals , Binding, Competitive , Cell Line, Tumor , Humans , Male , Muscle, Skeletal/anatomy & histology , Muscle, Skeletal/drug effects , Organ Size/drug effects , Oxazines/chemistry , Oxazines/pharmacology , Prostate/anatomy & histology , Prostate/drug effects , Quinolones/chemistry , Quinolones/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Transcriptional Activation/drug effectsABSTRACT
The highly functionalized [5.9.5] tricyclic framework resident in jatrophatrione (1) and citlalitrione (2) has been synthesized. The route begins with the tandem anionic oxy-Cope rearrangement/methylation/transannular ene cyclization of 21 and subsequent introduction of a conjugated enone double bond. Hydroxyl-directed 1,4-reduction of this functionality in 25 with LiAlH(4)/CuI/hexamethylphosphoramide/tetrahydrofuran sets the stage for the implementation of a Grob fragmentation and expedited generation of 27. Stereocontrolled intramolecular hydrosilylation allows for the subsequent introduction of a cyclic carbonate as in 53. This intermediate undergoes remarkably efficient, fully regiocontrolled Treibs reaction to generate 54, with this maneuver serving as a pivotal step for making 1 available five steps later. Treatment of 1 with m-chloroperbenzoic acid leads to 2, with attack occurring preferentially on a alpha-face of the double bond more remote to the carbonyl.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Diterpenes/chemical synthesis , Jatropha/chemistryABSTRACT
The highly functionalized [5.9.5] tricyclic framework resident in jatrophatrione (1) has been synthesized. The route begins with the tandem anionic oxy-Cope rearrangement/methylation/transannular ene cyclization of 5 and subsequent introduction of a conjugated enone double bond. Hydroxyl-directed 1,4-reduction of this functionality in 6 with LiAlH4/CuI/HMPA/THF sets the stage for the implementation of a Grob fragmentation and rapid generation of 8. Stereocontrolled intramolecular hydrosilylation allows for the subsequent introduction of a cyclic carbonate as in 11. This intermediate undergoes a remarkably smooth Treibs reaction to generate 12, thus serving as a pivotal step for making 1 available five steps later.
