Motonori Miyakawa

Synthesis of [125I]‐, [2H]‐, and [3H]‐Labeled 3‐Iodothyronamine (T1AM)

Abstract 3‐Iodothyronamine (T1AM) is a novel metabolite of thyroid hormone. In HEK‐293 cells expressing an orphan G‐protein coupled receptor, the trace amine receptor, T1AM, potently increased cAMP accumulation. In mice, T1AM rapidly induced hypothermia and bradycardia within minutes of administration. These results suggest the existence of a new signaling pathway, the stimulation of which leads to rapid physiological and behavioral consequences. Isotope‐labeled T1AM derivatives would be useful to study the biology and pharmacology of T1AM. Herein we describe efficient syntheses of [125I]‐, [2H]‐, and [3H]‐T1AM.

Trace amine-associated receptor 1 (TAAR1) is activated by amiodarone metabolites.

Amiodarone (Cordarone, Wyeth-Ayerst Pharmaceuticals) is a clinically available drug used to treat a wide variety of cardiac arrhythmias. We report here the synthesis and characterization of a panel of potential amiodarone metabolites that have significant structural similarity to thyroid hormone and its metabolites the iodothyronamines. Several of these amiodarone derivatives act as specific agonists of the G protein-coupled receptor (GPCR) trace amine-associated receptor 1 (TAAR(1)). This result demonstrates a novel molecular target for amiodarone derivatives with potential clinical significance.

Design and synthesis of tricyclic tetrahydroquinolines as a new series of nonsteroidal selective androgen receptor modulators (SARMs).

Some tricyclic tetrahydroquinolines (THQs) were found to have the potential of a new series of nonsteroidal selective androgen receptor modulators (SARMs). Compound 5b was first designed and synthesized under our hypothesis based on a four-point pharmacophoric requirement of the 3-carbonyl, 18-methyl, 17-hydroxyl, and 13-quaternary carbon groups of dihydrotestosterone (DHT). It was revealed that this compound exhibits not only a strong androgen receptor (AR) agonistic activity (EC(50)=9.2 nM) but also the highest selectivity in binding affinity to AR among the steroid hormone receptors. Furthermore, this compound showed a weak virilizing effect with retention of the desired anabolic effect as compared with DHT in vivo.

Tetrahydroquinolines as a novel series of nonsteroidal selective androgen receptor modulators: structural requirements for better physicochemical and biological properties.

A rationally designed tetrahydroquinoline (1) for nonsteroidal selective androgen receptor modulators was modified for the exploration of promising compounds by Grieco three-component condensation using various dienophiles. Based on the in vitro effects and physicochemical properties of the synthesized compounds, compound 4c was selected for further study. Compound 4c increased the femoral bone mineral density as much as DHT, but it reduced the uterus effect compared with DHT in ovariectomized rats. Thus, compound 4c has desirable osteoanabolic effects with weak undesirable effects on the uterus in a female osteoporosis model.

Lead Evaluation of Tetrahydroquinolines as Nonsteroidal Selective Androgen Receptor Modulators for the Treatment of Osteoporosis

Tetrahydroquinoline (THQ) was deemed to be a suitable scaffold for our nonsteroidal selective androgen receptor modulator (SARM) concept. We adapted the strategy of switching the antagonist function of cyano‐group‐containing THQ (CN‐THQ) to the agonist function and optimized CN‐THQ as an orally available drug candidate with suitable pharmacological and ADME profiles. Based on binding mode analyses and synthetic accessibility, we designed and synthesized a compound that possesses a para‐substituted aromatic ring attached through an amide linker. The long‐tail THQ derivative 6‐acetamido‐N‐(2‐(8‐cyano‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta[c]quinolin‐4‐yl)‐2‐methylpropyl)nicotinamide (1 d), which bears a para‐acetamide‐substituted aromatic group, showed an appropriate in vitro biological profile, as expected. We considered that the large conformational change at Trp741 of the androgen receptor (AR) and the hydrogen bond between 1 d and helix 12 of the AR could maintain the structure of the AR in its agonist form; indeed, 1 d displays strong AR agonistic activity. Furthermore, 1 d showed an appropriate in vivo profile for use as an orally available SARM, displaying clear tissue selectivity, with a separation between its desirable osteoanabolic effect on femoral bone mineral density and its undesirable virilizing effects on the uterus and clitoral gland in a female osteoporosis model.