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Drug Assays

How Close Do You Get to the Best Compound?

Here’s a topic that came up in my Twitter feed the other day – I fear it’s unanswerable, but I’d like to hear what people have to say about it. Drug discovery projects start, of course, from a selection of possible chemical matter and chemical series, and they eventually narrow down to a clinical candidate. Various possibilities are given an airing along the way, but the one that makes it through has to come reasonably close to satisfying a whole list of criteria – potency, selectivity, metabolic stability, toxicology, ease of formulation, and others. Some of these can be rather closely coupled, while others are unrelated to each other, and others may be actually opposed (for example, the structural changes that bring on more potency might be just the ones that lead to worse pharmacokinetics).

One question is, though, how many other compounds that would be “development-worthy” are still in there when the project finishes up? That could include ones that were made near the end and didn’t get a full hearing, but I think the question is more directed at analogs that never got made at all. I would guess that most projects could in theory be squeezed for another clinical candidate from their same chemical series – many times this might come from something that is more difficult to make at the bench and was thus not followed.

This is related to a question that’s come up around here before: if you took the same new drug target and set several organizations to working on it at the same time, with their own chemical screens and their own set of medicinal chemists, how many different chemotypes would result? That experiment has been done, quite a few times, under natural conditions, by companies working on the same target but not knowing what the competition was up to. (Coming at a target when you know something about the competing chemical matter is a different case – you’re deliberately trying to avoid the competing patent claims, and you’ll have made some of the other stuff as a comparison for your assays). But in the flying-blind situation, it seems to depend on what sort of SAR the target protein will tolerate. There are cases (such as the PPARs) where the binding pocket accommodates all sorts of stuff and a wide variety of chemical matter shows up, and others where things are so constrained that some common features are almost inevitable. There may be a narrow tunnel in the binding site, or a metal atom that you pretty much have to coordinate to, or a basic region that any potent compound is going to have an acidic group to match with, and so on,

The specific question that came up on Twitter, though, is an even higher bar: how many existing drugs have even *better* variations that just didn’t get pursued? I suppose an alternate way of asking this would be, if you could completely set aside worries about patent claims, how many existing drugs could be re-worked by varying their existing structures to find something better? That immediately suggests the follow-up question of “What do you mean by better?”, and that’s going to be different for different drugs. Could be better selectivity, longer half-life, more (or perhaps less!) potency, avoiding some specific metabolite, etc. There are some drugs that you look at and say “Actually, that one doesn’t really have so many problems”, but there are plenty of others that could in theory be tweaked to something a bit better.

I think the closest thing we have to a real-world example of this is the first wave of deuterated drug analogs. The idea there was that compounds whose biggest problem was metabolism (short half-life or a metabolite best avoided) could be improved by selective deuteration to slow down specific enzymatic bond-breaking events. And at the time, no one wrote their patent language to accommodate such deuterated analogs, so IP-wise the field was pretty open. That story continues: Teva got the first approval in 2017 for a deuterated version of an older compound. Concert Pharmaceuticals is a major player in that area, and they just announced clinical results the other day for a deuterated version of Incyte’s ruxolitinib. So the idea works, but at the same time it hasn’t revolutionized the drug industry, either.

And that’s my guess about the answer to the “better variations” question. I think that clinical candidates (and especially marketed compounds) are certainly at the far end of the big distribution, and that most improvements would probably be small. If a major liability is uncovered, that almost always happens in time for a program to either be killed or to reset and search for newer, better chemical matter. So what makes it out the far end is already pretty good – I think it’s unlikely that there are too many notably better compounds (for the same target) to be made by variations on known drug structures. Thoughts?

45 comments on “How Close Do You Get to the Best Compound?”

  1. CMCguy says:

    Due to time lags in prep and testing of analogs I have seen over a half dozen projects that came up with a probable “better compounds” after 1-2 leads have been selected and gone through animal testing. Generally these became the target back-up if there was early issues (ADME, Tox) with final candidate but never saw pursued because failures occurred later in Phase 1 or 2 that put in to question the whole MOA/series as viable drugs. Only an opinion based on observations and interaction with others as I would speculate most people and companies have had similar experiences where had timing and cost compromises prevented development of potentially better analog.

  2. cynical1 says:

    Everyone knows that data does not drive Candidate Selection. Politics does. The project team is going to pick the candidate that the project leader can claim as all their own to further their career. That’s the way it works.

    1. AVS-600 says:

      You should find a different place to work.

    2. Pajas says:

      Which company do you work for?

  3. Kelvin says:

    If you consider a drug’s properties like safety and efficacy then I think there is always a better variant out there somewhere. But if you factor in the cost of actually finding and developing it, then I think what we eventually end up with is often the best compromise in terms of overall return on investment. Which may be why return on investment is always declining by the law of diminishing returns?

    1. Chris Phoenix says:

      If most of the cost comes late in the game (clinical trials and marketing) then I don’t think your argument applies. If there are ten plausible candidates, you can take all ten through the earliest stages for relatively low cost, but you won’t take more than one through the trials that demonstrate it can be sold as a drug. So what’s the chance that you picked the best of the ten?

      1. tommysdad9 says:

        It won’t matter that you have best of the ten if 3 or 4 of your competitors beat you to market with “good enough” versions. It’s not only cost, but time.

  4. Eric says:

    Nearly every small molecule project I’ve worked on in my 20+ years has had backup compounds that look ‘better’ than the lead compound based upon potency or microsomal stability or some other early screening assay. Often the lead compound has already been declared a clinical candidate and is in the midst of IND-enabling studies when the backups are discovered. Inevitably, further work on the backup compounds stops and they sit on the shelve. It’s a train that’s already left the station and the ‘improved’ backups will never catch up unless the lead compound derails. What’s hard to predict is whether these compounds would have any meaningful benefit in the clinic. My suspicion is that there would only be incremental improvements, but who knows?

    1. Sken says:

      This is very similar to my experience, typically there is a point where you have to lock-in your research and development and move on to actually getting it manufactured and then into the clinic.

      Back ups and 2nd/3rd gen versions typically proceed at a slower pace or in my field (Biologics-conjugates) newer technology and better understanding is also applied to different projects when possible.

  5. InformationOrganizer says:

    Designer performance-enhancing and recreational drugs might be relevant to this topic. For example, the BALCO scandal, which involved a number of high-profile athletes. In that case, minor changes were made to an anabolic steroid to make it undetectable in tests with little or no impact on biological activity.

    I guess it could be considered “better” if avoiding drug tests is an endpoint!

  6. entropyGain says:

    my experience is it is always harder to make backups than the original candidate. Maybe its the extra constraint of chemically diversity from the lead.

    Cynical – if it’s really politics, then get the heck out of there and go someplace where the craftsmanship of medicinal chemistry matters. A candidate stands on the shoulders of all the failed molecules before it. In a functioning team, it’s luck of the draw who actually makes the ultimate candidate.

  7. Maybe, maybe not says:

    Isn’t the “best” compound determined by its clinical efficacy?
    And if so, are differences in clinical efficacy really predictable at the time of DC selection?

    We can rank-order compounds based on a design hypothesis… but to say that this will lead to a more efficacious compound, is just that: an hypothesis…

  8. Diver Dude says:

    In my experience, the best compounds are those that the patients will actually take. The ease of use and adverse event profile of the molecule are at least as important as clinical efficacy. Without the first two, you don’t get much of the third.

  9. one man CRO says:

    i just synthesized a d-11 analog of an FDA approved compound for the purpose of slowing clearance. the d-11 compound showed 40% increase in (rat) plasma concentration relative to the d-0 parent. i thought the idea was nutty but the compound is now going though cGMP production in route to the clinic.

  10. Wavefunction says:

    I think part of the dirty truth is that there are sometimes better compounds left behind on the table, and the best compound is not necessarily selected because it’s the “best” (although it’s usually not awful) but because someone on the team has enough leverage and prestige to push for it. Cases in which the best compound is marginally better than others are of course much more common (marketing essentially decides what’s the “best” compound in those cases).

  11. Eugene says:

    Better is the enemy of good enough.

    1. Mike W says:

      Shouldn’t that be “best” ?

      1. loupgarous says:

        Both of you are right. The wikipedia article “Perfect is the enemy of good” traces the aphorism to the opening of Voltaire’s poem La Bégueule

        Dans ses écrits, un sage Italien
        Dit que le mieux est l’ennemi du bien.

        – or, in English:

        “In his writings, a wise Italian says that the best is the enemy of the good”

        The wikipedia goes on to cite something more closely related to the question in this article:

        “The Pareto principle or 80–20 rule explains this numerically. For example, it commonly takes 20% of the full time to complete 80% of a task while to complete the last 20% of a task takes 80% of the effort.[5] Achieving absolute perfection may be impossible and so, as increasing effort results in diminishing returns, further activity becomes increasingly inefficient.”

  12. Calvin says:

    Interesting comments. The way I think about it, a project starts with loads of compounds being made and few assays. The make-test cycle is fairly short. But as a project gets further down the pipe and more of the desire properties are met the number of compounds made gets lower because you are trying to optimize very specific things (and they are always harder to make!). Tied to that is the reality that you can never bee too potent, and your DMPK/Tox can always be better. So we are always going to try to be better because we generally have no idea what good enough is, we’re guessing (unless we’re patent busting something already in the clinic and which seems to work). So I think candidates happen when a project team becomes convinced that they’ve plateued. They have a bunch of compounds that seem to have the best balance and in the months after they have been made they keep passing the various tests we set. In those intervening months we’re searching for something “better” but if the top compound isn’t failing and the new compounds don’t provide some breakthrough past the plateau then we kinda know we’re as good as we can get. And of course the more data we generate on the candidate the less shiny it becomes and the warts become obvious; we often never find out if the backups have warts too; they have pristine shiny data and look fabulous. So I think that there are cases where backups were “better” but at some point you’ve got to take a run at the clinical part with something you really believe could work (not kid yourself) and not having blown through all your cash. I think we can all agree it’s a fun game.

  13. Peter S. Shenkin says:

    As has been at least implied by others, you don’t really know if your approved drug is so great until it’s been approved and out in the field for years, and most of the time you never find that out for the backup candidates.

    But I do wonder whether any of those candidates left behind ever were revived and approved as drugs following the patent expiration of the original winner, or following the withdrawal of the original winner from the market due to issues that became apparent only in widespread use. If so, and the revived backup candidate survived its full patent term, you would likelyl conclude that it was a better drug than the original winner which it replaced.

    1. gcc says:

      I’d be very interested in hearing if there are known examples of this as well.

      1. White on Black says:

        Not quite what you’re asking, gcc, but here’s a story anyway, at least as far as I came to understand it. There may of course be other hidden wrinkles I didn’t hear about, as there often are. Back before my time at the company(s) I once worked for, a better selectivity drug followed on from a first in class drug so significant its prime creator got a Nobel Prize 20 years later.

        The better selectivity drug had passed all the regulatory requirements. A year or so after launch all was going well, until in real-life patients, mostly elderly, serious adverse effects on eyes and vision began to come to light. By all accounts this eye toxicity couldn’t have been predicted using the accepted models and tests of the day and was in no way related to the drug’s MOA.

        A catastrophe which haunted the company for years to come, in the era after thalidomide and before Opren. A PR disaster around that time involving smoking beagles didn’t help corporate and scientific confidence either. For the research site, Paradise Lost forever.

        The company withdrew the drug forthwith. A flap was on to find a replacement asap. Patients, revenues and reputations, corporate and individual, depended on it. Enter stage left to the rescue Dr Serendipity, on white charger, with sword aloft and in full shining armour.

        25 Years later I shared an office with a named inventor on the substance patent who related the inside story on the quiet. Project in the mire. Target compound, target of the section manager’s drug design, not obtained. Unexpected side product obtained instead. Side product had all the desired features and facets and a few more thrown in for good measure too. Duly became a blockbuster.

        Crowded and complicated patent area subject to legal challenges, as rival organisations tried to muscle in on something that shouldn’t have been theirs to have, in other words tried to get some much needed revenues on the cheap. That’s business for you.

        Scientists and expert witnesses up before beaks in wigs on both sides of the pond. After years and years before beaks, beaks and more beaks, phew, at last, side product signed off as an unexpected observation and hence invention (or legalese to that effect). Argument won the day, industrial property duly ring fenced and protected as specified by patent laws. Happiness on site all round and in main boardroom too. Well done, chaps.

        So there it is. Of course everyone’s a lot cleverer nowadays and dull old Dr Serendipity got pensioned off years ago. Everything gets done in an innovative, well planned, rational and full rationalised way doesn’t it, just like it says on those artily seductive corporate websites..?

        Although if you’ve time, dear corporate website designers, do please dig out and reflect some time on those lines from Holmes to Dear Watson back in the days before the Wright brothers, words to the effect being about flying above Victorian London streets like birds and spotting all the unknown little connections and coincidences you couldn’t see right in front of you when striding boldly and purposefully along those fogbound London streets, umbrella tips clacking on cobblestones, all set on solving your latest strange case…

  14. Dominic Ryan says:

    A related question is can a given LO program find the ‘best’ compound. One way to answer that question is to look at the next, related, compounds on the market. They usually come from a different company. One example is cimetidine (Tagament, discovered by J. Black at Smith Kline and French) and ranitidine (Zantac, discovered at Glaxo). Check Wiki for structures to see how similar they are. Ranitidine came on the market some 5 years after cimetidine. It improved the P450 inhibition profile quite a lot and ultimately significantly displaced Tagamet.
    All this happened a few years before I started at SmithKline Beecham and I was told (have not investigated) that the patent for cimetidine left open holes that made it possible to patent ranitidine. Perhaps that’s true but the main point is that SKB had not found the ‘best’ compound. Since then a number of other H2 antagonists were developed with an even better P450 profile.
    In those days peptic ulcer was a major indication. Later it the role of helicobacter pylorii was discovered and that changed the landscape again.
    Black won the Nobel in 1988, in part for the H2 discovery. With that Tagamet changed the landscape. Was it the ‘best’? The right antibiotic can clear helicobacter, is that the ‘best’ compound for the actual indication?
    The question is clearly complicated.
    I think one of the main lessons is that the chemical universe is vast and there is likely some other way of hitting any given target, perhaps with a better compound.
    Within a project team medchem is really quite good now at mapping out the local chemistry space. I don’t know how to draw the line between them though.

    Basically, this is hard.

    1. RHB says:

      Pretty sure I was there in the labs in converted old warehouses next to an old canal when what grew up to be ZANTAC was first synthesised, registered and tested back in 1977. Nowt to do with me I hasten to add, and to be absolutely sure I was there I’d need to know if the first registration date was prior to early September of that year.

      According to Wikipedia, Zantac’s birth name was AH19065, which tells the future blockbuster was conceived, registered and first brought up by ALLEN and HANBURYS, then as I recall run as a parallel research organisation to GLAXO.

      Corporate family history then tells that two years later ALLEN and HANBURYS and GLAXO begat GLAXO GROUP RESEARCH, which not long after married WELLCOME to become GLAXO WELLCOME, which not long after that…

      …Committed bigamy with a serial bigamist known as SMITH KLINE BEECHAM (poor dear French having been Shanghaid, a quaint old phrase from a century or more ago that now barely even registers on Google, which fate of course later befell poor old Beecham too, and which fate has been getting worse and worse ever since right up to this very day, or so they say…). The rest, as they say, is bickering. And sorry, Captain Corante, if I’ve gone too over the top into a great British institution here. If so, please censor.

      Fond memories indeed of the ALLEN and HANBURYS research group, which a few years earlier had also come up with salbutamol (Ventolin inhaler). Two big drugs in just over a decade at a research site with a pretty small footprint, now just an imprint on history.

      As I assume is the croquet lawn which used to be on the A&H site, just behind the restaurant. You win again, Frank Ellis. And well done Larry Lunts, John Pickering, John Bradshaw and many, many more. May the force go with you.

      1. Diver Dude says:

        I interviewed at Allen and Hanburys in ’89 but joined Wellcome instead. The croquet lawn by the Mansion at Beckenham was excellent and the site of many deadly Clinical Pharmacology Dept duels. If you look on Google Maps, it is still there.

        1. RHB says:

          Looks on Google Earth like neat grass square of right size still next to Allenburys Sports and Social Club. The A&H croquet lawn lives on.

          Interesting that two small and productive research sites both had croquet lawns. Sort of Intelligence CEOs pay handsomely for. Order up the croquet lawns HR.

          CEO readers please pipe up. Advice FOC, instead of paying clever young things from McKinsey millions…

      2. toluene says:

        Ahhh–the good old days when launch parties were “Launch Parties”. Fond memories of starting out in “L” lab when A&H was writing the book on 5HT pharmacology.

  15. Frans Haber says:

    I think you get closer to the “best” compound for projects coming from Big Pharma. For biotech, usually the first compound that shows acceptable potency and has measurable exposure in rodent is nominated. Someone high up is aware of at least one example of an approved drug with CL > 90% Qh and therefore this must be “good enough” for all drugs. Timelines are “met,” the company becomes “clinical stage” and the money rolls in! The higher ups are off to their next position based on their great success getting a compound into the clinic (in record time!) before they have to answer for any of it.

  16. Barry says:

    We had what we were convinced was an exciting clinical candidate at the time that we brought in a new Head of Research. He announced that nothing would go forward that didn’t have a half-life in mice of 2hr, and couldn’t be dissuaded. Some months later, we had wrapped our molecule in teflon (7 C-F bonds) at the expense of only a little affinity and a bit of selectivity to satisfy his ukase. And there it stood at the moment we were acquired. Our new corporate masters had their own project on the same target, so were not immediately interested in our chemical matter. When they did look, they looked at the best-characterized compound (i.e. the one with 2hr half-life in mice) and quickly determined that its PK was unmanageable. They never even looked at our better cmpds.

  17. Watson says:

    In the end, the best compound is the one with the lowest NNT and LD50. Or at least that’s what I thought it was all about.

    1. Barry says:

      No one tests LD50 in humans (and a higher LD50 would be better, all other things being equal)

      1. loupgarous says:

        “No one tests LD50 in humans…”

        …but some folks came pretty close to it.

  18. petros says:

    We certainly had better compounds than one that I worked on which is approved. The key factor was that the approved drug was already in man, having originally been intended for a different indication. It was felt that a bird in the hand was better than a drug that was more potent, and selective for the desired indications, in animals but which was at least 3 years behind in the development phase

  19. milkshake says:

    I worked on backup series to Sutent. Our compound SU14813 got into clinic but Pfizer eventually shelved it because it did not have a clear clinical advantage over Sutent, and it had to be dosed twice a day. The difference was only in the sidechain, which affected metabolism and PK but not the kinase selectivity (the drug is notoriously nonselective, first-gen inhibitor). The problems with Sutent that got addressed in the backup – nonlinear dose/response, organ accuumulation and long lived active metabolite that was cardiotoxic (QT prolongation) turned out to be manageable in the patients,

    1. Anonymous says:

      Sutent, SUGEN: I think his statement has been more accurately documented elsewhere, but I was at a seminar where Schlessinger, a co-founder of SUGEN, said something like, very liberally paraphrased, ‘It’s easy to get funding once you’ve made a drug. They throw money at you because they believe that you will do it again.’

  20. Anonymous says:

    I think the question can be partially answered by historical studies of successful drugs. Pregabalin was one of the very first compounds prepared in a series of GABA analogs. The IP was licensed by Parke-Davis and many more (100s? more that 500 more?) analogs were prepared and studied. Nothing outperformed pregabalin and that was that. Librium was the “last” compound made in a series that was supposed to be a quinazoline. It underwent a rearrangement and became one of the first benzodiazepine drugs. (Note: benzodiazepines were known in the literature long before Sternbach’s discovery which occurred in the different context of drug discovery.) Librium may have been first in class but it has been superseded by many other benzodiazepines with improved properties.

    This historical approach can’t address failed (unpublished; not well known) research programs that were aborted one compound short of a blockbuster … because that compound was never allowed to be made and we’ll never know about it.

    Very small structural changes can produce huge effects, but (1) you can’t always accurately predict the effect and (2) you can’t make every compound.

    The “magic methyl” has been previously discussed In The Pipeline and I repeat something I posted before: Methyl Effects on Protein–Ligand Binding. Jorgensen, et al. J. Med. Chem., 2012, 55 (9), pp 4489–4500, DOI: 10.1021/jm3003697 says:

    “The effects of addition of a methyl group to a lead compound on biological activity are examined. A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is found with an 8% frequency, and a 100-fold boost is a 1 in 200 event. …” in the abstract, but further down is the key thing I remembered (my [emph] added):

    “The key observations from the survey are that on average in reported SAR series introduction of a methyl group is [[[ just as likely to hurt as help activity ]]] and that it is extremely rare for addition of a methyl group to give a free energy gain greater than 3 kcal/mol; in fact, only 4 of the 2145 cases are in this category. …”

    Of course, the data set will always be biased by what info the authors choose to disclose about their Me vs des-Me analogs. From published data, you can determine whether it is a Magic Methyl or a Miserable Methyl but you can’t say anything about the unpublished Secret Methyl.

    My final comment is about the philosophical nature of such a question itself. We won’t ever know an as yet unknown “better” drug until it is made and approved. Any number of newer, poorer analogs doesn’t prove that the current best is actually the best. We can only know current best (or current mediocre for some drugs) and try to work past that.

  21. Dr Sternberg says:

    Mention of the drug LIBRIUM prompts a literari historyan to report recent recovery from a memory stick of an original digital record from the late 1990s, the authentic script of a play in 5 acts entitled The Librarium Story.

    The ins and outs of the original strange story of the discovery of LIBRIUM in the 1950s had been reported over 20 years later with unusually intimate honesty and vividity by the one and only Dr Leo Sternbach, named inventor on the LIBRIUM substance patent and lead chemist in what became known as THE BENZODIAZEPINE STORY.

    Dr Sternbach told The BENZODIAZEPINE Story as the ACS Award Address at the 16th ACS Medicinal Chemistry Symposium in Kalamazoo, Michigan, on June 20 1978. A condensed version of the address later appeared in the one and only J Med Chem (1979, 22, 1-7).

    Any In the Pipeline readers present in the audience in Kalamazoo over 40 years ago, please post a comment! Dr Sternbach wrote up the story again for a 1979 article in Chemtech entitled, “STORM BEFORE THE CALM.”

    The first and last performance of the play The Librarium Story took place in a small provincial theatre in North West England on Tuesday 27th January 1998 at 12 midday GMT. The action takes place in two scientific laboratories on either side of the Atlantic Ocean.

    All 5 acts were played out on a stage set out as a meeting room designated 3S115, laid out with a typical meeting room table and 6 matching chairs, which also served as the seating arrangements for the audience of 6, who also doubled up as the 7 parts in the play, two of the parts being taken by an actor-director named Leo Sternberg…

    …Who played one part as himself and the other part as a British scientific consultant named Professor Moriarty. A whiteboard, magic markers and a whiteboard cleaner were the only props. Other characters in the play were two Englishmen named Hemlock Clones and Dr Whatson, and three Americans named Elliott Nest, Louise Layne and Bud Attman.

    Space constraints preclude entering herein a full transcript of all 5 acts of the play. By way of a taster, the literari historyan has given kind permission for inclusion of the front page of the programme for the first and only performance. Make of it what you will…


    A re-working in 5 acts of a classic drama of structure revision, drug discovery and nice crystals, from New Jersey in the 1950s, that all started in Heidelberg in 1891…

    ACT I: November 1958, Stoneleigh Park, England: “You do realise, my dear Whatson, this stuff could be like a bottle of Scotch but without the hangover – Dosche certainly won’t give us any so we’ll have to make it ourselves!”

    ACT II: July 1954, Dosche Laboratories, New Jersey: “We could not think of an intelligent working hypothesis…”

    ACT III: May 1955: “In the midst of our work, we began to have serious doubts about the structure…”

    ACT IV: April-June 1957: “Our intensive work on antibiotics, of little practical value, finally led to an almost hopeless situation. The laboratory benches were covered with dishes, flasks, and beakers – all containing various samples and mother liquors. The working area had shrunk almost to zero, and a major spring cleaning was in order…”

    ACT V: January 1998, Stoneleigh Park, England: Now mostly long retired, and amidst longstanding stockmarket rumour that their two companies may unite, the surviving scientists meet in a recently opened, luxury state of the art conference facility, known as 3S115.

    Literari historyan postscriptum: Same rumour, different company, came true later that year. The end of normal life as Z******s knew it. The rest, as they say, is historia et histoirie…

    1. Pps says:

      For any literary critics who happen to read the above comment, the LH should also add: Act I imagination, Acts II-IV re-creation, Act V tried to be real life fun (maybe even a little educational, certainly was for the long lost playwright…).

      The LH has also uncovered an A4 ring binder with spine labelled “The Benzodiazepine Story,” that’s been buried for years inside an antiquated metal filing cabinet, tucked away in a corner of an unofficial artefact archive. The LH reports the ancient A4 ring binder, still in remarkably good condition considering the environs of the unofficial archive, contains photocopies of relevant patents and chemistry journal publications, annotated in places by a yellow highlighter pen.

      Not much more than that a playwright can do to delve deeper, other than maybe heading off to New Jersey hunting for any surviving protagonists (or more likely their descendants), or maybe even taking a look at a research site in New Jersey that maybe no longer exists, that maybe once held a stack of relevant historical documents, such as lab notebooks and associated original chemical and biological data…

      …Which on reflection, if still extant at all are more likely to be retained in the archives of a company still headquartered in a historically neutral country in the heart of central Europe. Now there’s an interesting thought.

  22. loupgarous says:

    A side trip to Dosche UK’s facility in Wartfordshire might not be totally wasted effort. I was there as a contract worker when they bought Sintechs (“the names have been changed to protect the innocent, if any of them can be found… ” Jimmy Buffett, Foolbutton). A lot of experimental pharm data flowed through the VAX and IBM legacy systems there.

    1. Ppps says:

      Now that’s interesting, Loupgarous, very interesting. Wartfordshire much closer to home. Coincidentally, decades ago Dr Sternberg travelled to now extinct volcano called Sintexica and heard legend of yam root from Mexican ravine, and all that truly wondrous find led to.

      Some story. Stuff of novels. Truth can be stranger than fiction. Now, hint of dodgy dossier material that lurked in Wartfordshire on VAX and IBM legacy systems? Ascent of Naproxicotecahito anyone?

      1. loupgarous says:

        Oh, no, not dodgy material (at least none of the trials I saw there were). Dosche UK was as non-dodgy as large pharma concerns get.

        But, anyone interested in tracing the history of benzodiazepines as tranquilizers might do well to check those archives.

        1. Pppps says:

          Understood. Dr S out of line to infer aspersions on Dosche or Sintechs clinical data – not Dr S’s strong point at all.

  23. Rx developer says:

    How you end depends on how you start. More often than not, a candidate won’t be too different from the starting point , so a strong indicator of success is a good starting point’for chemistry. That, and really understanding mechanism of action and dosing.

    1. milkshake says:

      I agree – the best starting point for a medchem project is 1) A target with well established cell based and animal models that already gave you a drug 2) Screening hit compound derived from a drug, or an older drug candidate (that was already in the clinic)

  24. Benissimo says:

    I’d be willing to bet good money that we never get the best possible compound. My money’s safe because no-one can disprove this, but in any case. Even if we made every possible compound in an area (which we don’t), and if we got every bit of standard in vitro data we could on all of them (which we can’t), and progressed everything that had a chance into our PK and PD models (!) and selected the best compound from all that… none of that perfectly predicts what compound would be “best” (whatever that means) in a real life clinical population. There’s just too many things about how a compound works in a population of people to predict accurately. There’s a danger of spending too long sometimes “polishing” to try and find a perfect compound based on always-flawed and incomplete data. Find a compound good enough to test your clinical hypothesis, get it in the clinic as soon as possible.

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