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  • E7080 mg Based on structure activity relationship of several

    2024-03-30

    Based on structure activity relationship of several SARM templates, Ligand Pharmaceuticals chose LGD2226 as their first clinical candidate (Miner et al., 2007). Although LGD2226 demonstrated myo- and osteo-anabolic activity and maintenance of sexual function in various preclinical models, the development of LGD2226 was discontinued. Ligand advanced another molecule LGD2941 to phase I clinical trials for frailty and osteoporosis in collaboration with Takeda Abbott pharmaceuticals. To date, there isn't any evidence that this and other SARMs developed by Ligand have advanced further. Other companies such as Merck (Schmidt et al., 2010), Glaxo, Johnson and Johnson, Orion, and Pfizer all pursued SARM development during the late 1990s and the first decade of 2000s. Preclinical results from each of the optimized scaffolds demonstrated potent tissue-selectivity and anabolic activity. However, most, if not all, of these compounds failed to advance to clinical development either due to toxicity or lack of efficacy, or other undisclosed reasons. The structure of various SARM templates is provided in Fig. 1.
    Mechanisms for SARM tissue-selectivity The molecular mechanisms underlying the separation of the detrimental androgenic activities (e.g., virilization/prostatic hypertrophy) from the desired anabolic effects remain unknown. While the SERMs have been investigated for decades, studies to characterize the molecular mechanisms of action of SARMs have only been initiated more recently. Several mechanisms such as the coactivator-corepressor ratio and tissue-selective modulation of signaling pathways that have been established as mechanisms for the tissue-selectivity of SERMs are also applicable to the SARMs (Smith and O'Malley, 2004, Smith et al., 1997). The tissue-selective expression of ER-isoforms, (ER-α and ER-β), that often have distinct responses to ligand and thereby provide tissue-selective modulation of ER function by SERMs is unique to SERMs (Madeira et al., 2013). A variety of other molecular mechanisms likely contribute to the observed tissue-selectivity of SARMs. Enzymes: Although the tissue-specific expression of various steroidogenic and metabolic E7080 mg does not sufficiently explain characterized differences between the pharmacology of steroidal androgens and SARMs, it can account for the amplification and inactivation of steroidal androgens observed in some tissues (Gao and Dalton, 2007). One of the enzymes, 5α-reductase, converts testosterone into more potent DHT in some tissues (e.g., prostate and skin) but not others (e.g., muscle and bone), representing a tissue specific amplification of steroidal ligands in prostate and other tissues that does not contribute to nonsteroidal SARM action. Expression of other enzymes belonging to hydroxysteroid dehydrogenase (HSD) class regulates the availability of steroidal androgens to the AR in a variety of tissues. The enzymes 3-α HSD and 3-β HSD convert DHT to 3-α and 3-β diols, respectively (Blouin et al., 2006). Both of these DHT metabolites are weaker AR ligands compared to testosterone or DHT. Considering that the 3-α and 3-β HSDs are bifunctional enzymes, the tissue-specific expression and directionality of function ultimately regulate AR activity. Other androgen-synthesizing enzymes 17-β HSD types 3 and 5 are highly expressed in testes and prostate and they play important roles in synthesizing testosterone from precursor androstenedione (Labrie et al., 1997, Penning and Byrns, 2009). Interestingly, most SARMs developed are non-steroidal and are not thought to be susceptible to enzymatic metabolism in target tissues and hence retain their activity in all the tissues wherever they are bioavailable. Coregulator Function. More than 200 AR-interacting proteins (both coactivators and corepressors) (Chang and McDonnell, 2005, Heinlein and Chang, 2002), including those with intrinsic functions such as histone acetyl transferase activity (SRCs, CBP) (Smith and O'Malley, 2004), histone deacetylase activity (NCoR, SMRT) (Smith and O'Malley, 2004), and other chromatin modifying functions (SWI/SNF/BRG) (Smith and O'Malley, 2004), have been identified. In addition to several coactivators that are shared by other steroid receptors, a few coactivators such as the ARA family members that exclusively activate the AR have been reported to be expressed in tissues such as prostate (Fujimoto et al., 1999, Kang et al., 1999). The AR differs from other receptors in its interaction with coregulators. The LBD of the AR has 11 anti-parallel helices, unlike other receptors that contain 12 helices as the AR is devoid of helix 2, that undergo significant rearrangement upon ligand binding creating a shallow hydrophobic pocket to facilitate association with the NTD of the AR or coactivators containing an LxxLL motif (Heery et al., 1997, Shiau et al., 1998). While the coactivator interaction surface in other class I receptors exists in the AF-2 in the LBD, the coactivator interaction surface in the AR exists in the AF-1 (Heinlein and Chang, 2002, He et al., 2002).