Disposition and Metabolism of LY2452473, a Selective Androgen Receptor Modulator, in Humans

Abstract

ABSTRACT:The disposition and metabolism of isopropyl N-[(2S)-7-cyano-4-(2-pyridylmethyl)-2,3-dihydro-1H-cyclopenta[b]indol-2-yl]carbamate (LY2452473; a selective androgen receptor modulator) in humans was characterized after a single 15-mg (100 Ci) oral dose of [ 14 C]LY2452473 to six healthy male subjects. LY2452473 was absorbed rapidly (time to reach maximum plasma concentration for both LY2452473 and total radioactivity was 2-3 h) and cleared slowly (plasma terminal t 1/2 of 27 h for LY2452473 and 51 h for the total radioactivity). LY2452473 and metabolites S5 (acetylamine) and S12 (hydroxylation on the cyclopentene) were major circulating entities in plasma, accounting for approximately 42, 21, and 35% of the total radioactivity exposure, respectively, as calculated from relative area under the concentration versus time curves from zero to 48 h derived from the plasma radiochromatograms. The radioactive dose was almost completely recovered after 312 h with 47.9% of the dose eliminated in urine and 46.6% in feces. Minimal LY2452473 was detected in excreta, indicating that metabolic clearance was the main route of elimination. Multiple metabolic pathways were observed with no single metabolic pathway accounting for more than 30% of the dose in excreta. Metabolite S10 (a diol across the cyclopenta-indole linkage) was the largest excretory metabolite (approximately 14% of the dose). S10 displayed interesting chemical and chromatographic properties, undergoing conversion to the corresponding epoxide under acidic conditions and conversion back to the diol under neutral conditions. An in vitro phenotyping approach indicated that CYP3A4 was the largest contributor to LY2452473 depletion.

Organocatalytic Asymmetric Cascade Reactions of 7‐Vinylindoles: Diastereo‐ and Enantioselective Synthesis of C7‐Functionalized Indoles

“…Subsequently, the ratio of reagents 1 a and 2 a was modified, but no further improvement in the yield was obtained (entries 9-11). Moreover, the effect of catalyst loading on the reaction was investigated (entries [12][13][14], which revealed that 5 mol % of 4 d could catalyze the reaction just as well as 10 mol % of 4 d (entry 12 versus entry 1), but that increasing the catalyst loading could improve the yield and the enantioselectivity (entries 13 and 14 versus entry 1). Finally, a catalyst loading of 15 mol % 4 d was regarded as optimal for its good performance in raising the yield to 68 % with a retained excellent stereoselectivity of > 95:5 d.r.…”

“…This structure is also present in many natural alkaloids and bioactive molecules. [12] Herein, we report the first catalytic asymmetric cascade reactions of 7-vinylindoles, which have been accomplished through the rational design of such substrates. Such cascade reactions with 3-indolylmethanols in the presence of a chiral phosphoric acid allow the diastereo-and enantioselective synthesis of C7functionalized indoles as well as the construction of cyclopen-ta[b]indole and spirooxindole frameworks (all > 95:5 d.r., 94-> 99 % ee).…”

Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer

“…1) [25,[32][33][34][35][36], clinical efficacy data have only been reported for LGD-4033 (Ligand Pharmaceuticals, one Phase I trial), MK-0773 (Merck & Co., one Phase II trial), and enobosarm (GTx, Inc., one Phase I and two Phase II trials). 1) [25,[32][33][34][35][36], clinical efficacy data have only been reported for LGD-4033 (Ligand Pharmaceuticals, one Phase I trial), MK-0773 (Merck & Co., one Phase II trial), and enobosarm (GTx, Inc., one Phase I and two Phase II trials).…”

Selective androgen receptor modulators: comparative excretion study of bicalutamide in bovine urine and faeces

“…[7] While in Europe, growth promoters have been banned for use in food-producing animals since 1988 (Council Directive 88/146/EEC prohibiting the use livestock farming of certain substances having a hormonal action 1988), strategies to detect potential SARMs misuse in livestock production are urgently required to guarantee consumers of food from animal origin free of any residues of such compounds. Furthermore, and because it has been demonstrated in different species that SARMs were eliminated in the faeces, [9,[22][23][24][25][26][27][28][29][30] the present work aims at studying faeces as an alternative interesting biological matrix to detect these substances in livestock. [18,19] Since these compounds have recently emerged, they have not been investigated a lot.…”

“…We therefore propose in this study to investigate further SARMs elimination and metabolism in bovine. Furthermore, and because it has been demonstrated in different species that SARMs were eliminated in the faeces, [9,[22][23][24][25][26][27][28][29][30] the present work aims at studying faeces as an alternative interesting biological matrix to detect these substances in livestock. Faeces is indeed an easy-to-collect matrix and its relevance in livestock for detecting some residues or metabolites of growth promoters has already been demonstrated.…”