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Has Anyone Tried Rad-140?
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<blockquote data-quote="madman" data-source="post: 150799" data-attributes="member: 13851"><p>Be aware that this paper is based on animals.....not humans!</p><p></p><p></p><p></p><p></p><p><strong>Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (<span style="color: rgb(184, 49, 47)">SARM</span>) <span style="color: rgb(184, 49, 47)">RAD140</span> </strong></p><p></p><p></p><p></p><p><strong>ABSTRACT </strong></p><p><strong>This report<span style="color: rgb(184, 49, 47)"> describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). </span><span style="color: rgb(26, 188, 156)">The characterization of RAD140 in several preclinical models of anabolic androgen action is also described. </span></strong></p><p></p><p></p><p></p><p><strong>Our work in the <span style="color: rgb(184, 49, 47)">SARM</span> area resulted in the synthesis and evaluation of a large number of candidate templates.</strong> <span style="color: rgb(184, 49, 47)"><strong>While we found it relatively easy to obtain compounds with high affinity for AR, </strong></span><span style="color: rgb(44, 130, 201)"><strong>we struggled to achieve compounds that demonstrated good oral efficacy and high in vivo tolerability.</strong></span> <strong>After scanning many potential leads for<span style="color: rgb(184, 49, 47)"> oral, in vivo activity</span>, <span style="color: rgb(44, 130, 201)">we arrived at high affinity </span><span style="color: rgb(184, 49, 47)">compound5 </span><span style="color: rgb(44, 130, 201)">through a combination of synthetic intermediate testing, literature evaluation and fragment combination.</span> We were delighted when <span style="color: rgb(184, 49, 47)">5 </span>demonstrated <span style="color: rgb(184, 49, 47)">oral activity in rats.</span></strong></p><p></p><p><strong>However, when we performed <span style="color: rgb(184, 49, 47)">a pharmacokinetic analysis in rats, we could detect only very low levels of 5 after oral dosing (F < 5%). </span>Further analysis revealed that<span style="color: rgb(184, 49, 47)"> 5 was efficiently converted to </span><span style="color: rgb(44, 130, 201)">6 </span><span style="color: rgb(184, 49, 47)">in vivo</span>, presumably by <span style="color: rgb(184, 49, 47)">cytochromes P450 in the rat liver.</span> <span style="color: rgb(44, 130, 201)">Compound 6</span> had similar activity to <span style="color: rgb(184, 49, 47)">compound 5</span> in vivo, suggesting that <span style="color: rgb(44, 130, 201)">6 was largely responsible for the activity </span>of <span style="color: rgb(184, 49, 47)">compound 5.</span> An in vitro screen with human microsomes revealed <span style="color: rgb(184, 49, 47)">rapid metabolism of compound 5</span>, thus indicating this transformation as <span style="color: rgb(184, 49, 47)">a potential human metabolic liability</span> and prompting us to prepare<span style="color: rgb(44, 130, 201)"> compounds in which the 40 -position of the pendant phenyl was blocked from P450-induced hydroxylation.</span> We looked at <span style="color: rgb(184, 49, 47)">several analogues containing a 40 -blocking group</span>, and in the course of our efforts we <span style="color: rgb(26, 188, 156)">identified compound 7 </span><span style="color: rgb(0, 0, 0)">(</span><span style="color: rgb(26, 188, 156)">RAD140; Figure 1</span><span style="color: rgb(0, 0, 0)">) </span>as our <span style="color: rgb(184, 49, 47)">preclinical development candidate. </span></strong></p><p></p><p><strong>The <span style="color: rgb(26, 188, 156)">synthesis of compound 7</span> is shown in <span style="color: rgb(184, 49, 47)">Scheme 1.</span> <span style="color: rgb(184, 49, 47)">We relied on an expeditious, ipso-fluorine substitution of the left-hand side precursor, piece 8, with D-threonine in the presence of K2CO3 in DMSO to give the desired </span></strong><span style="color: rgb(251, 160, 38)"><strong>product 9 </strong></span><strong><span style="color: rgb(184, 49, 47)">in workable yields </span></strong><span style="color: rgb(0, 0, 0)"><strong>(</strong></span><span style="color: rgb(251, 160, 38)"><strong>typically >50%</strong></span><span style="color: rgb(0, 0, 0)"><strong>).</strong></span> <strong>The D-Thr adduct 9 was coupled with 4-cyanobenzohydrazide under standard coupling conditions using EDCI and HOBt. The resultant<span style="color: rgb(243, 121, 52)"> product 10</span> was silylated with TBDMS-Cl, subjected to dehydrative cyclization conditions in the presence of TPP/I2, and then desilyated for the final step. Overall, this has proven to be <span style="color: rgb(184, 49, 47)">a reliable and efficient synthesis</span> using a <span style="color: rgb(184, 49, 47)">fairly inexpensive, albeit nonproteinogenic amino acid</span> as the chirality source.</strong></p><p></p><p><strong>The <span style="color: rgb(44, 130, 201)">stability</span> <span style="color: rgb(26, 188, 156)">of</span> <span style="color: rgb(26, 188, 156)">RAD140</span> was high (t1/2 >2h) in incubations with rat, monkey, and human microsomes, and it also had <span style="color: rgb(44, 130, 201)">good bioavailability</span><span style="color: rgb(184, 49, 47)"> in rats (F = 27-63%) and monkeys (65-75%). </span><span style="color: rgb(26, 188, 156)">RAD140</span> demonstrated <span style="color: rgb(44, 130, 201)">excellent affinity</span><span style="color: rgb(184, 49, 47)"> for the androgen receptor (Ki = 7 nM vs 29 nM for testosterone and 10 nM for DHT) </span>as well as <span style="color: rgb(44, 130, 201)">good selectivity</span><span style="color: rgb(184, 49, 47)"> over other steroid hormone nuclear receptors</span>, with the closest off target receptor being the progesterone receptor (IC50 = 750 nM vs 0.2 nM for progesterone). In vitro functional androgen agonist activity was confirmed in the C2C12 osteoblast differentiation assay, where an EC50 of 0.1 nM was shown (DHT=0.05 nM). </strong></p><p></p><p></p><p></p><p></p><p><strong><span style="color: rgb(184, 49, 47)">Clinical chemistry </span>indicated the expected <span style="color: rgb(44, 130, 201)">lowering of lipids (LDL, HDL, triglycerides).</span> Despite the rather dramatic increases in body weight over such a short time, there was no elevation of liver enzyme transaminase levels in any animal at any dose >2 fold over its baseline value. </strong>Given the well-established relationship between oral androgen use and liver stress indicators, we were quite pleased that at a dose 10-fold greater than the fully effective dose we saw minimal liver enzyme elevations.Taken in sum, <strong><span style="color: rgb(26, 188, 156)">RAD140 </span><span style="color: rgb(184, 49, 47)">has all the hallmarks of a SARM. </span>It is <span style="color: rgb(44, 130, 201)">potency selective</span>, since it <span style="color: rgb(44, 130, 201)">stimulates muscle weight increases at a lower dose</span> <span style="color: rgb(184, 49, 47)">than that required to stimulate prostate weight increases.</span></strong> <strong>Moreover, it is also <span style="color: rgb(44, 130, 201)">efficacy selective</span>, because it is <span style="color: rgb(44, 130, 201)">fully anabolic on muscle </span>but demonstrates l<span style="color: rgb(26, 188, 156)">ess than complete efficacy on the prostate and seminal vesicles</span> and, in fact, <span style="color: rgb(44, 130, 201)">can partially antagonize the stimulation of the seminal vesicles induced by testosterone</span></strong><span style="color: rgb(44, 130, 201)">. </span><strong><span style="color: rgb(26, 188, 156)">RAD140</span> <span style="color: rgb(44, 130, 201)">has</span> <span style="color: rgb(44, 130, 201)">excellent pharmacokinetics and is a potent anabolic</span><span style="color: rgb(184, 49, 47)"> in nonhuman primates as well.</span> We believe the <span style="color: rgb(184, 49, 47)">overall preclinical profile of </span><span style="color: rgb(26, 188, 156)">RAD140</span><span style="color: rgb(184, 49, 47)"> is very good</span>, and <span style="color: rgb(44, 130, 201)">the compound has completed preclinical toxicology in both rats and monkeys.</span></strong> <strong><span style="color: rgb(184, 49, 47)">We are currently preparing</span><span style="color: rgb(26, 188, 156)"> RAD140 </span>for<span style="color: rgb(26, 188, 156)"> phase I clinical studies</span> <span style="color: rgb(184, 49, 47)">in patients suffering from severe weight loss due to cancer cachexia. </span></strong></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p><strong><span style="color: rgb(184, 49, 47)">Figure1. </span>Structures of testosterone (1), </strong><span style="color: rgb(71, 85, 119)"><strong>5R-dihydrotestosterone (2)</strong></span><strong> ,<span style="color: rgb(147, 101, 184)">GTxS-22 (3)</span>, <span style="color: rgb(243, 121, 52)">BMS 562929 (4)</span>, <span style="color: rgb(184, 49, 47)">initial lead 5</span>, <span style="color: rgb(44, 130, 201)">active metabolite 6</span>, <span style="color: rgb(26, 188, 156)">and 7 (RAD140).</span></strong></p><p>[ATTACH=full]7608[/ATTACH]</p><p></p><p></p><p><strong><span style="color: rgb(184, 49, 47)">Scheme 1.</span> Synthesis of <span style="color: rgb(26, 188, 156)">Compound 7 (RAD140)</span></strong></p><p>[ATTACH=full]7609[/ATTACH]</p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p><span style="color: rgb(0, 0, 0)">This is the only and the first human study using</span><strong> <span style="color: rgb(26, 188, 156)">RAD140 </span>(<span style="color: rgb(184, 49, 47)">PHASE I</span>)</strong></p><p></p><p></p><p><span style="font-size: 26px"><strong>Phase 1, First-in-Human Study of RAD140 in Postmenopausal Women With Breast Cancer</strong></span></p><p></p><p></p><p></p><p><strong>Sponsor: </strong></p><p><strong><span style="color: rgb(184, 49, 47)">Radius Pharmaceuticals, Inc.</span></strong></p><p></p><p><strong>Information provided by (Responsible Party):</strong></p><p><strong><span style="color: rgb(184, 49, 47)">Radius Pharmaceuticals, Inc.</span></strong></p><p></p><p></p><p></p><p></p><p></p><p><a href="https://www.clinicaltrials.gov/ct2/show/NCT03088527?term=rad140&rank=1" target="_blank">Phase 1, First-in-Human Study of RAD140 in Postmenopausal Women With Breast Cancer - Full Text View - ClinicalTrials.gov</a></p><p></p><p></p><p></p><p></p><p></p><p>[ATTACH=full]7607[/ATTACH]</p><p></p><p></p><p></p><p></p><p>It would also most likely have a strong negative effect on lowering of lipids when higher doses are used which many end up doing when cycling SARMS!</p></blockquote><p></p>
[QUOTE="madman, post: 150799, member: 13851"] Be aware that this paper is based on animals.....not humans! [B]Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator ([COLOR=rgb(184, 49, 47)]SARM[/COLOR]) [COLOR=rgb(184, 49, 47)]RAD140[/COLOR] [/B] [B]ABSTRACT This report[COLOR=rgb(184, 49, 47)] describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). [/COLOR][COLOR=rgb(26, 188, 156)]The characterization of RAD140 in several preclinical models of anabolic androgen action is also described. [/COLOR][/B] [B]Our work in the [COLOR=rgb(184, 49, 47)]SARM[/COLOR] area resulted in the synthesis and evaluation of a large number of candidate templates.[/B] [COLOR=rgb(184, 49, 47)][B]While we found it relatively easy to obtain compounds with high affinity for AR, [/B][/COLOR][COLOR=rgb(44, 130, 201)][B]we struggled to achieve compounds that demonstrated good oral efficacy and high in vivo tolerability.[/B][/COLOR] [B]After scanning many potential leads for[COLOR=rgb(184, 49, 47)] oral, in vivo activity[/COLOR], [COLOR=rgb(44, 130, 201)]we arrived at high affinity [/COLOR][COLOR=rgb(184, 49, 47)]compound5 [/COLOR][COLOR=rgb(44, 130, 201)]through a combination of synthetic intermediate testing, literature evaluation and fragment combination.[/COLOR] We were delighted when [COLOR=rgb(184, 49, 47)]5 [/COLOR]demonstrated [COLOR=rgb(184, 49, 47)]oral activity in rats.[/COLOR][/B] [B]However, when we performed [COLOR=rgb(184, 49, 47)]a pharmacokinetic analysis in rats, we could detect only very low levels of 5 after oral dosing (F < 5%). [/COLOR]Further analysis revealed that[COLOR=rgb(184, 49, 47)] 5 was efficiently converted to [/COLOR][COLOR=rgb(44, 130, 201)]6 [/COLOR][COLOR=rgb(184, 49, 47)]in vivo[/COLOR], presumably by [COLOR=rgb(184, 49, 47)]cytochromes P450 in the rat liver.[/COLOR] [COLOR=rgb(44, 130, 201)]Compound 6[/COLOR] had similar activity to [COLOR=rgb(184, 49, 47)]compound 5[/COLOR] in vivo, suggesting that [COLOR=rgb(44, 130, 201)]6 was largely responsible for the activity [/COLOR]of [COLOR=rgb(184, 49, 47)]compound 5.[/COLOR] An in vitro screen with human microsomes revealed [COLOR=rgb(184, 49, 47)]rapid metabolism of compound 5[/COLOR], thus indicating this transformation as [COLOR=rgb(184, 49, 47)]a potential human metabolic liability[/COLOR] and prompting us to prepare[COLOR=rgb(44, 130, 201)] compounds in which the 40 -position of the pendant phenyl was blocked from P450-induced hydroxylation.[/COLOR] We looked at [COLOR=rgb(184, 49, 47)]several analogues containing a 40 -blocking group[/COLOR], and in the course of our efforts we [COLOR=rgb(26, 188, 156)]identified compound 7 [/COLOR][COLOR=rgb(0, 0, 0)]([/COLOR][COLOR=rgb(26, 188, 156)]RAD140; Figure 1[/COLOR][COLOR=rgb(0, 0, 0)]) [/COLOR]as our [COLOR=rgb(184, 49, 47)]preclinical development candidate. [/COLOR][/B] [B]The [COLOR=rgb(26, 188, 156)]synthesis of compound 7[/COLOR] is shown in [COLOR=rgb(184, 49, 47)]Scheme 1.[/COLOR] [COLOR=rgb(184, 49, 47)]We relied on an expeditious, ipso-fluorine substitution of the left-hand side precursor, piece 8, with D-threonine in the presence of K2CO3 in DMSO to give the desired [/COLOR][/B][COLOR=rgb(251, 160, 38)][B]product 9 [/B][/COLOR][B][COLOR=rgb(184, 49, 47)]in workable yields [/COLOR][/B][COLOR=rgb(0, 0, 0)][B]([/B][/COLOR][COLOR=rgb(251, 160, 38)][B]typically >50%[/B][/COLOR][COLOR=rgb(0, 0, 0)][B]).[/B][/COLOR] [B]The D-Thr adduct 9 was coupled with 4-cyanobenzohydrazide under standard coupling conditions using EDCI and HOBt. The resultant[COLOR=rgb(243, 121, 52)] product 10[/COLOR] was silylated with TBDMS-Cl, subjected to dehydrative cyclization conditions in the presence of TPP/I2, and then desilyated for the final step. Overall, this has proven to be [COLOR=rgb(184, 49, 47)]a reliable and efficient synthesis[/COLOR] using a [COLOR=rgb(184, 49, 47)]fairly inexpensive, albeit nonproteinogenic amino acid[/COLOR] as the chirality source.[/B] [B]The [COLOR=rgb(44, 130, 201)]stability[/COLOR] [COLOR=rgb(26, 188, 156)]of[/COLOR] [COLOR=rgb(26, 188, 156)]RAD140[/COLOR] was high (t1/2 >2h) in incubations with rat, monkey, and human microsomes, and it also had [COLOR=rgb(44, 130, 201)]good bioavailability[/COLOR][COLOR=rgb(184, 49, 47)] in rats (F = 27-63%) and monkeys (65-75%). [/COLOR][COLOR=rgb(26, 188, 156)]RAD140[/COLOR] demonstrated [COLOR=rgb(44, 130, 201)]excellent affinity[/COLOR][COLOR=rgb(184, 49, 47)] for the androgen receptor (Ki = 7 nM vs 29 nM for testosterone and 10 nM for DHT) [/COLOR]as well as [COLOR=rgb(44, 130, 201)]good selectivity[/COLOR][COLOR=rgb(184, 49, 47)] over other steroid hormone nuclear receptors[/COLOR], with the closest off target receptor being the progesterone receptor (IC50 = 750 nM vs 0.2 nM for progesterone). In vitro functional androgen agonist activity was confirmed in the C2C12 osteoblast differentiation assay, where an EC50 of 0.1 nM was shown (DHT=0.05 nM). [/B] [B][COLOR=rgb(184, 49, 47)]Clinical chemistry [/COLOR]indicated the expected [COLOR=rgb(44, 130, 201)]lowering of lipids (LDL, HDL, triglycerides).[/COLOR] Despite the rather dramatic increases in body weight over such a short time, there was no elevation of liver enzyme transaminase levels in any animal at any dose >2 fold over its baseline value. [/B]Given the well-established relationship between oral androgen use and liver stress indicators, we were quite pleased that at a dose 10-fold greater than the fully effective dose we saw minimal liver enzyme elevations.Taken in sum, [B][COLOR=rgb(26, 188, 156)]RAD140 [/COLOR][COLOR=rgb(184, 49, 47)]has all the hallmarks of a SARM. [/COLOR]It is [COLOR=rgb(44, 130, 201)]potency selective[/COLOR], since it [COLOR=rgb(44, 130, 201)]stimulates muscle weight increases at a lower dose[/COLOR] [COLOR=rgb(184, 49, 47)]than that required to stimulate prostate weight increases.[/COLOR][/B] [B]Moreover, it is also [COLOR=rgb(44, 130, 201)]efficacy selective[/COLOR], because it is [COLOR=rgb(44, 130, 201)]fully anabolic on muscle [/COLOR]but demonstrates l[COLOR=rgb(26, 188, 156)]ess than complete efficacy on the prostate and seminal vesicles[/COLOR] and, in fact, [COLOR=rgb(44, 130, 201)]can partially antagonize the stimulation of the seminal vesicles induced by testosterone[/COLOR][/B][COLOR=rgb(44, 130, 201)]. [/COLOR][B][COLOR=rgb(26, 188, 156)]RAD140[/COLOR] [COLOR=rgb(44, 130, 201)]has[/COLOR] [COLOR=rgb(44, 130, 201)]excellent pharmacokinetics and is a potent anabolic[/COLOR][COLOR=rgb(184, 49, 47)] in nonhuman primates as well.[/COLOR] We believe the [COLOR=rgb(184, 49, 47)]overall preclinical profile of [/COLOR][COLOR=rgb(26, 188, 156)]RAD140[/COLOR][COLOR=rgb(184, 49, 47)] is very good[/COLOR], and [COLOR=rgb(44, 130, 201)]the compound has completed preclinical toxicology in both rats and monkeys.[/COLOR][/B] [B][COLOR=rgb(184, 49, 47)]We are currently preparing[/COLOR][COLOR=rgb(26, 188, 156)] RAD140 [/COLOR]for[COLOR=rgb(26, 188, 156)] phase I clinical studies[/COLOR] [COLOR=rgb(184, 49, 47)]in patients suffering from severe weight loss due to cancer cachexia. [/COLOR][/B] [B][COLOR=rgb(184, 49, 47)]Figure1. [/COLOR]Structures of testosterone (1), [/B][COLOR=rgb(71, 85, 119)][B]5R-dihydrotestosterone (2)[/B][/COLOR][B] ,[COLOR=rgb(147, 101, 184)]GTxS-22 (3)[/COLOR], [COLOR=rgb(243, 121, 52)]BMS 562929 (4)[/COLOR], [COLOR=rgb(184, 49, 47)]initial lead 5[/COLOR], [COLOR=rgb(44, 130, 201)]active metabolite 6[/COLOR], [COLOR=rgb(26, 188, 156)]and 7 (RAD140).[/COLOR][/B] [ATTACH=full]7608[/ATTACH] [B][COLOR=rgb(184, 49, 47)]Scheme 1.[/COLOR] Synthesis of [COLOR=rgb(26, 188, 156)]Compound 7 (RAD140)[/COLOR][/B] [ATTACH=full]7609[/ATTACH] [COLOR=rgb(0, 0, 0)]This is the only and the first human study using[/COLOR][B] [COLOR=rgb(26, 188, 156)]RAD140 [/COLOR]([COLOR=rgb(184, 49, 47)]PHASE I[/COLOR])[/B] [SIZE=26px][B]Phase 1, First-in-Human Study of RAD140 in Postmenopausal Women With Breast Cancer[/B][/SIZE] [B]Sponsor: [COLOR=rgb(184, 49, 47)]Radius Pharmaceuticals, Inc.[/COLOR][/B] [B]Information provided by (Responsible Party): [COLOR=rgb(184, 49, 47)]Radius Pharmaceuticals, Inc.[/COLOR][/B] [URL='https://www.clinicaltrials.gov/ct2/show/NCT03088527?term=rad140&rank=1']Phase 1, First-in-Human Study of RAD140 in Postmenopausal Women With Breast Cancer - Full Text View - ClinicalTrials.gov[/URL] [ATTACH=full]7607[/ATTACH] It would also most likely have a strong negative effect on lowering of lipids when higher doses are used which many end up doing when cycling SARMS! [/QUOTE]
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