Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play a critical role in the regulation of glucose (RXR/PPARgamma) and lipid metabolism (RXR/PPARalpha). Previously, we described a concise structure-activity relationship study of selective RXR modulators possessing a (2E,4E,6Z)-3-methyl-7-(3,5-dialkyl-6-alkoxyphenyl)-octa-2,4,6-trienoic acid scaffold. These studies were focused on the 2-position alkoxy side chain. We describe here the design and synthesis of a novel series of RXR selective modulators possessing the same aromatic core structure with the addition of a ring locked 6-7-Z-olefin on the trienoic acid moiety. The synthesis and structure-activity relationship studies of these 6,7-locked cyclopentenyl, phenyl, thienyl, furan, and pyridine-trienoic acid derivatives is presented herein.

Dedicated to Professor Albert Eschenmoser on the occasion of his 75th birthdayWe have completed the total syntheses of elastase inhibitors YM-47141 and YM-47142, the first natural products containing a vicinal tricarbonyl group. The work establishes the configuration at C(4) of the macrocyclic depsipeptide and demonstrates the generality of the phosphoranylidene-ylide activation and protection methodology employed earlier in syntheses of a-keto amides. Key steps involve the coupling of a carboxylic acid with a phosphorane to form a stable ylide intermediate, which contains the highly electrophilic carbonyl group in protected form. The tricarbonyl unit was unmasked at the final stage of the synthesis by oxidative cleavage of the CP bond.

A series of androgen receptor modulators based on 8H- [1,4]oxazino[2,3-f]quinolin-8-ones was synthesized and evaluated in an androgen receptor transcriptional activation assay. The most potent analogues from the series exhibited single-digit nanomolar potency in vitro. Compound 18h demonstrated full efficacy in the maintenance of muscle weight, at 10 mg/kg, with reduced activity in prostate weight in an in vivo model of androgen action.The androgen receptor (AR) is a member of the intracellular receptor superfamily of liganddependent transcription factors. 1 The endogenous ligands for AR are the steroids testosterone (T) and dihydrotestosterone (DHT). When bound to AR, these ligands play important roles in sexual development and function, 2 and musculo-skeletal growth. 3 Steroidal androgen therapy is effective for the treatment of androgen insufficiency. However, the broader use of these androgens for additional treatments, such as osteoporosis or frailty, is limited by undesirable AR-mediated effects, such as prostatic hypertrophy and hirsutism. A selective androgen receptor modulator (SARM), with full anabolic activity but reduced impact on the undesirable effects could have a large role on endocrine therapies to treat muscle wasting and osteoporosis. 4 Early studies on modified androgens explored alkylation at C-17, as in fluoxymesterone (1 , Figure 1). 5 However, compounds from this general class are associated with potential liver toxicity. 2 Recent publications in the area of nonsteroidal androgens is indicative of the high level in discovering novel safe, effective anabolic agents (2, 3). [6][7][8] Our continued interest in SARMs is based on scaffolds derived from quinolin-2-ones (4 and 5). 9,10 During the course of our studies on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones (5a), we isolated as a minor byproduct of the Knorr quinolone reaction 11 regioisomer (6a, <5% yield, Scheme 1) which fortuitously possessed AR agonist activity in a transcriptional activation assay (78% agonist efficacy, 5 nM). Investigations into the scaffold led to a series of novel androgens derived from 8H-[1,4]oxazino[2,3-f]quinolin-8-ones (6). The lead compound from this series, 18h, demonstrated full efficacy in the maintenance of levator ani weight (LA) muscle, an anabolic endpoint in a castrated mature rat model.Our previous investigations of quinolinone scaffolds 4 and 5 revealed that the regions proximal to the tertiary amine group strongly affected AR activity. Consequently, we sought to probe

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