Sm04554

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  • KO1
    Senior Member
    • Jan 2012
    • 805

    #61
    Cotsarelis should become aware of this drug.

    Comment

    • charlie76761
      Member
      • Oct 2014
      • 60

      #62
      Thanks for this Boldy - will see if i can find out any results with 6-bio but would presume no otherwise if wouldnt have escaped the normal hype! but that's not to say it couldnt still work...

      Dont suppose you know anything abut SM04554 in terms of structure?

      May be a bit tenuous, but believe i've found the patent but lacks molecular structure apparently



      i think this is the compound being used in Samumed's SM trials in San Diegeo - one the lead inventors listed on the patent works for Samumed as per https://www.linkedin.com/pub/sunil-kumar-kc/3/934/149 and the patent seems relevant in it's description

      Further, looks the most likely from the other patents he's developed http://www.faqs.org/patents/inventor...an-diego-us-1/

      Thoughts?

      Comment

      • Swooping
        Senior Member
        • May 2014
        • 794

        #63
        I suppose it is either compound 1 , 2 or 3. But can't know for sure.. Compound 2 seems the most strongest from their essay.

        Administration and Pharmaceutical Compositions

        [0317] Some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound according to Formulas I, II or III, or its corresponding enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier.

        Comment

        • Tenma
          Senior Member
          • Nov 2013
          • 172

          #64
          Boldy, why do you think SM4554 wont regrowth much hair on its own? Maybe using it in conjuction with DUT or RU could be better?

          Comment

          • Tenma
            Senior Member
            • Nov 2013
            • 172

            #65
            Maybe you are comparing sm potential effectiveness with VPA based on that small scale trial published some time ago.

            I think the trial had some important limitations.

            According the investigators “the optimal dose and concentration of the VPA spray were not determined and higher concentration and dose of the VPA spray may be more effective for the treatment of AGA.”

            "Of the 40 patients enrolled in the study, 27 (n = 15, VPA group; n = 12, placebo group) completed the entire protocol with good compliance."

            27 is a really small sample size

            Comment

            • inbrugge
              Senior Member
              • Oct 2013
              • 244

              #66
              And in the meanwhile we continue to grow balder...lol

              Comment

              • Boldy
                Senior Member
                • Jan 2013
                • 287

                #67
                Originally posted by Tenma
                Boldy, why do you think SM4554 wont regrowth much hair on its own? Maybe using it in conjuction with DUT or RU could be better?
                because we have had really potent gsk3b inhibitors (6-bio) this year, with limited results, although, it is not good to draw a conclusion on small group of people who tried it about 5-10.

                6-bio ic50 is about 5nm
                Lithium 2mm


                with other words 6-bio is about 40.000 times stronger/ more selective in vitro.

                as you can see it is really hard to out perform 6bio..


                we might have to give it an another try with dermarolling or other mechanisms.


                @ charlie I will look to the patent of smo, it might be logical to assume that they took compound 2, however it is not necessary that they picked compound 2, other factors play a role too like toxicology and binding on other receptor sites.

                Comment

                • KO1
                  Senior Member
                  • Jan 2012
                  • 805

                  #68
                  To be fair though, I believe lithium's potency in vivo exceeds its potency in vitro....that being said, I agree that just upregulating Wnt doesn't really solve the major problem of pushing the SC's to produce TACs...


                  Check out this....even more potent GSK-3b modulators than 6-BIO
                  The serine/threonine kinase glycogen synthase kinase-3 beta (GSK3b) is a known master regulator for several cellular pathways that include insulin signaling and glycogen synthesis, neurotrophic factor signaling, Wnt signaling, neurotransmitter signaling and microtubule dynamics. Consequently, this enzyme has been implicated in multiple human disorders including Alzheimer’s disease, bipolar disorder, noninsulin-dependent diabetes mellitus, cardiac hypertrophy, and cancer. Precisely how GSK3b maintains its pathway specificity efficiently at the crossroads of many cellular processes is still unclear. Many inhibitors of GSK3b exist, however these compounds have been found lacking in selectivity, with CHIR 99021 considered most potent and selective. The goal for this project is to identify potent and highly selective small molecule probes to investigate GSK3b biology in cellular and ultimately in whole animal models. A library of over three hundred twenty thousand compounds was screened against human GSK3b. Among the inhibitors identified, CID 5706819 showed decent potency and excellent selectivity inhibiting only five out of over three hundred kinases at 10 μM by over fifty percent. Subsequent chemical modifications of CID 5706819, guided by a co-crystal structure with GSK3b, and a battery of biochemical and cell-based assays led to CID 56840716/ML320 that inhibits GSK3b at IC50 between 10–30 nM. ML320 has a superior kinome-wide selectivity profile compared to CHIR99021. Further, ML320 demonstrates excellent cellular activity in inhibiting GSK3b-mediated Tau phosphorylation in SH-SY5Y neuroblastoma cells (IC50 of 1 μM), and in relieving negative regulation by GSK3b on cellular beta-catenin degradation and TCF/LEF promoter activities with EC50 of 5 μM in both assays. At the same time, no cellular toxicity by ML320 was observed in SH-SY5Y cells at the highest testing concentration of 30 μM. Taken together, ML320 is a potent and highly selective small molecular probe against GSK3b, allowing better investigation and interpretation of GSK3b cellular functions than the existing prior art. ML320 scaffold also holds the promise to deliver additional compounds with further improved biochemical, cellular, and pharmacokinetic properties suitable for investigating in vivo roles of GSK3b in pertinent animal physiology and pathology.


                  I

                  Comment

                  • Gjm127
                    Senior Member
                    • Mar 2012
                    • 170

                    #69
                    Originally posted by charlie76761
                    i think this is the compound being used in Samumed's SM trials in San Diegeo - one the lead inventors listed on the patent works for Samumed as per https://www.linkedin.com/pub/sunil-kumar-kc/3/934/149 and the patent seems relevant in it's description
                    Thoughts?
                    Yeah! All makes sense, I had called the CB clinic in SD and the woman told me that in a month they'll be starting a new exciting treatment trial for hair loss but wouldn't give any specifics... This confirms that it was effectively SM that she was talking about!!!

                    All in all: The SD clinic is recruiting for CB and SM trials!

                    Comment

                    • Tenma
                      Senior Member
                      • Nov 2013
                      • 172

                      #70
                      Originally posted by Gjm127
                      Yeah! All makes sense, I had called the CB clinic in SD and the woman told me that in a month they'll be starting a new exciting treatment trial for hair loss but wouldn't give any specifics... This confirms that it was effectively SM that she was talking about!!!

                      All in all: The SD clinic is recruiting for CB and SM trials!
                      Good to hear.

                      2016 will be THE year for us. I'm more excited about Sm though. Since Hamilton studies in the 60s we know the therapeutic limits of the antiandrogenic angle (very little regrowth, long term maintenance).

                      WNT agonists and or GSK-3 inhibitors with wounding are the most promising things in the pipeline.

                      All that said, unlike others, i think CB will be released for AGA and it should be the really really effective for those young men intelligent enough to start using it at the very early stages of aga.

                      Comment

                      • Boldy
                        Senior Member
                        • Jan 2013
                        • 287

                        #71
                        Originally posted by KO1
                        To be fair though, I believe lithium's potency in vivo exceeds its potency in vitro....that being said, I agree that just upregulating Wnt doesn't really solve the major problem of pushing the SC's to produce TACs...


                        Check out this....even more potent GSK-3b modulators than 6-BIO
                        The serine/threonine kinase glycogen synthase kinase-3 beta (GSK3b) is a known master regulator for several cellular pathways that include insulin signaling and glycogen synthesis, neurotrophic factor signaling, Wnt signaling, neurotransmitter signaling and microtubule dynamics. Consequently, this enzyme has been implicated in multiple human disorders including Alzheimer’s disease, bipolar disorder, noninsulin-dependent diabetes mellitus, cardiac hypertrophy, and cancer. Precisely how GSK3b maintains its pathway specificity efficiently at the crossroads of many cellular processes is still unclear. Many inhibitors of GSK3b exist, however these compounds have been found lacking in selectivity, with CHIR 99021 considered most potent and selective. The goal for this project is to identify potent and highly selective small molecule probes to investigate GSK3b biology in cellular and ultimately in whole animal models. A library of over three hundred twenty thousand compounds was screened against human GSK3b. Among the inhibitors identified, CID 5706819 showed decent potency and excellent selectivity inhibiting only five out of over three hundred kinases at 10 μM by over fifty percent. Subsequent chemical modifications of CID 5706819, guided by a co-crystal structure with GSK3b, and a battery of biochemical and cell-based assays led to CID 56840716/ML320 that inhibits GSK3b at IC50 between 10–30 nM. ML320 has a superior kinome-wide selectivity profile compared to CHIR99021. Further, ML320 demonstrates excellent cellular activity in inhibiting GSK3b-mediated Tau phosphorylation in SH-SY5Y neuroblastoma cells (IC50 of 1 μM), and in relieving negative regulation by GSK3b on cellular beta-catenin degradation and TCF/LEF promoter activities with EC50 of 5 μM in both assays. At the same time, no cellular toxicity by ML320 was observed in SH-SY5Y cells at the highest testing concentration of 30 μM. Taken together, ML320 is a potent and highly selective small molecular probe against GSK3b, allowing better investigation and interpretation of GSK3b cellular functions than the existing prior art. ML320 scaffold also holds the promise to deliver additional compounds with further improved biochemical, cellular, and pharmacokinetic properties suitable for investigating in vivo roles of GSK3b in pertinent animal physiology and pathology.


                        I
                        agree Ko1, but if a compound can inhibit at uM dose, then its already ultra potent..


                        I still think that we could expect something from wounding/ Chlorine Dioxide + strong gsk3 inhibitors.

                        Comment

                        • KO1
                          Senior Member
                          • Jan 2012
                          • 805

                          #72
                          We need something more than dermarolling, I think. Cotsarelis' work implied that we need a wound that doesn't close in on itself, so a pinprick style wound like needle woulnd't do it. We need to dermabrade a decent surface area, say a few square cm's. Something like a chemical peel would work. Especially if we're doing this on slick bald scalp.

                          Comment

                          • KO1
                            Senior Member
                            • Jan 2012
                            • 805

                            #73
                            What do you guys think about using a topical like VPA or 6BIO to the donor site after FUE? All those wounds are there....

                            Comment

                            • sdsurfin
                              Senior Member
                              • Sep 2013
                              • 702

                              #74
                              Why do you guys think this SM drug will not work on its own? I'm assuming samumed has some hopes for efficacy if they are going ahead with such a large phase 2 trial...

                              I feel like I read a lot of armchair science on here, but as far as I know none of the guys on here have ever seen a wnt agonist used and tested in this capacity. whatever chemical you used is not the same as this one. I'm not saying I have high hopes for anything, but why exactly should we be skeptical of this one? Seems far more promising as a maintenance drug than CB or other antiandrogens, which have well known limitations.

                              Comment

                              • Tenma
                                Senior Member
                                • Nov 2013
                                • 172

                                #75
                                Originally posted by sdsurfin
                                Why do you guys think this SM drug will not work on its own? I'm assuming samumed has some hopes for efficacy if they are going ahead with such a large phase 2 trial...

                                I feel like I read a lot of armchair science on here, but as far as I know none of the guys on here have ever seen a wnt agonist used and tested in this capacity. whatever chemical you used is not the same as this one. I'm not saying I have high hopes for anything, but why exactly should we be skeptical of this one? Seems far more promising as a maintenance drug than CB or other antiandrogens, which have well known limitations.
                                Maybe SM04554 alone can regrow a good amount of hair on diffuse thinners? lets hope thats the case. I certainly dont expect a NW 7 to NW1 reversal.

                                But, like you said, they are spending millions on a ph.II trial for a reason. Also that trial will be 3 times bigger than the one cosmo is conducting for cb. Expensive as f#ck...

                                Nevertheless, after reading Boldy and seeing some great results with a proper wounding protocol, i think our best chance to regrow a good amount of hair will come from the combination of wounding and potent GSK3 inhibitors.

                                Comment

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