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From Blog: The Haystack

Heptares solves first X-ray structure of Family B GPCR, but full details not yet public

GPCR family tree

The new structure adds a new section of GPCR space amenable to computer modeling (big blue circle), a space which includes sought-after drug targets. Previously determined GPCR structures, which are all from the same family, are highlighted in small blue and red circles. Image courtesy Heptares

In what might be the year’s biggest molecular teaser, Heptares Therapeutics has announced that it has solved the first X-ray crystal structure of a G-protein coupled receptor in the Family B subclass. The work provides the first structural insights into a protein family that includes sought-after drug targets such as GLP-1 for diabetes and CGRP for migraine.

Largely because of that drug discovery relevance, however, Heptares is choosing to keep its structure somewhat close to the vest. Officials presented views of the structure, of a GPCR called Corticotropin Releasing Factor (CRF-1) receptor, at conferences on Friday and Monday. But Heptares CEO Malcolm Weir says his team has no immediate plans to publish the structure or to deposit coordinates into the repository known as the Protein Data Bank.

The structure, Weir says, is another success for Heptares’ GPCR stabilizing technology, StaR. The technique involves targeted mutations that help to trap a GPCR in a single biologically-relevant state. In the case of CRF-1, Weir says, the stabilized receptor is captured in the “off” state.

The structure itself, which is at a resolution of 3 Ångstroms, has the 7-helix membrane-spanning structure typical of GPCRs. However, CRF-1′s architecture is rather different from receptors in Family A, the only GPCR family for which X-ray structures had been available until now, Weir says. “The overall shape of the receptor looks different, the orientation of the helices looks different, and there are detailed differences within helices that are at analogous positions in Family A receptors,” he says. He notes that there are differences in helices 6 and 7, which undergo important motions during GPCR activation.

“This is an important breakthrough, although fine details of the structure and release of coordinates may still be some time away,” says Monash University’s Patrick Sexton, an expert in Family B GPCRs who was at Friday’s talk. The structure, he says, confirmed researchers’ expectations that the major differences in membrane-spanning helices between Family A and Family B receptors would occur on the extracellular side. “There was a very open and relatively deep extracellular binding pocket, with the receptor having a ‘V’ shaped appearance,” he says. This open pocket likely contributes to medicinal chemists’ difficulties obtaining high affinity small molecule ligands for Family B receptors, he suggests.

That open pocket might be involved in another Family B GPCR mystery, according to Roger Sunahara, also in attendance Friday, who studies GPCRs’ molecular mechanisms at the University of Michigan, Ann Arbor. All Family B GPCRs, including CRF-1, have a large domain at their amino-terminus that contains large portions of their ligand binding sites. That domain was not included in this structure, he says, but “it would appear that deleted globular N-terminal domain would fit quite nicely into the open pocket.”

The CRF-1 receptor is a drug target for depression and anxiety, but at least one CRF antagonist failed to show benefit compared to placebo in a clinical trial. Weir says the impact of the CRF-1 structure for drug discovery will not necessarily be in CRF-1 drug discovery per se, but in the ability to develop relevant computer models of related targets.

It hasn’t been possible to make accurate models of Family B receptors with Family A information, explains Ryan G. Coleman, a postdoctoral fellow at UCSF who develops GPCR models, but who was not in attendance at the talks. Quality models could streamline small molecule drug discovery for the entire family, he explains. Most of the natural ligands for Family B receptors are long peptides, which are notoriously tough to replace with small molecule drugs.

Experts like Coleman will have to wait for some time to learn about the structure for themselves, unless they happened to have a friend in the audience at Heptares’ talks. It’s not unheard of for there to be a gap of several months to two years between a structure’s announcement and publication.

“We’re delighted to have such an informative structure,” Weir says. “It’s very exciting.” He adds says Heptares is progressing toward a structure of the biggest fish in family B, GLP-1, in the “on” state.

From Blog: The Haystack

Haystack 2011 Year-in-Review

Well, 2011 is in the books, and we here at The Haystack felt nostalgic for all the great chemistry coverage over this past year, both here and farther afield. Let’s hit the high points:

1. HCV Takes Off – New treatments for Hepatitis C have really gained momentum. An amazing race has broken out to bring orally available, non-interferon therapies to market. In October, we saw Roche acquire Anadys for setrobuvir, and then watched Pharmasset’s success with PSI-7977 prompt Gilead’s $11 billion November buyout.  And both these deals came hot on the heels of Merck and Vertex each garnering FDA approval for Victrelis and Incivek, respectively, late last spring.

2. Employment Outlook: Mixed – The Haystack brought bad employment tidings a few times in 2011, as Lisa reported. The “patent cliff” faced by blockbuster drugs, combined with relatively sparse pharma pipelines, had companies tightening their belts more than normal. Traffic also increased for Chemjobber Daily Pump Trap updates, which cover current job openings for chemists of all stripes. The highlight, though, might be his Layoff Project.  He collects oral histories from those who’ve lost their jobs over the past few years due to the pervasive recession and (slowly) recovering US economy.. The result is a touching, direct, and sometimes painful collection of stories from scientists trying to reconstruct their careers, enduring salary cuts, moves, and emotional battles just to get back to work.

3. For Cancer, Targeted Therapies – It’s also been quite a year for targeted cancer drugs. A small subset of myeloma patients (those with a rare mutation) gained hope from vemurafenib approval. This molecule, developed initially by Plexxikon and later by Roche / Daiichi Sankyo, represents the first success of fragment-based lead discovery, where a chunk of the core structure is built up into a drug with help from computer screening.From Ariad’s promising  ponatinib P2 data for chronic myeloid leukemia, to Novartis’s Afinitor working in combination with aromasin to combat resistant breast cancer. Lisa became ‘xcited for Xalkori, a protein-driven lung cancer therapeutic from Pfizer. Researchers at Stanford Medical School used GLUT1 inhibitors to starve renal carcinomas of precious glucose, Genentech pushed ahead MEK-P31K inhibitor combinations for resistant tumors, and Incyte’s new drug Jakifi (ruxolitinib), a Janus kinase inhibitor, gave hope to those suffering from the rare blood cancer myelofibrosis.

4. Sirtuins, and “Stuff I Won’t Work With  – Over at In the Pipeline, Derek continued to chase high-profile pharma stories. We wanted to especially mention his Sirtris / GSK coverage (we had touched on this issue in Dec 2010). He kept up with the “sirtuin saga” throughout 2011, from trouble with duplicating life extension in model organisms to the Science wrap-up at years’ end. Derek also left us with a tantalizing tidbit for 2012 – the long-awaited “Things I Won’t Work With” book may finally be coming out!

5. Active Antibacterial Development – In the middle of 2011, several high-profile and deadly bacterial infections (Germany, Colorado, among others) shined a spotlight on those companies developing novel antibacterials. We explored front -line antibiotics for nasty Gram-negative E.coli, saw FDA approval for Optimer’s new drug Fidiclir (fidaxomicin) show promise against C. difficile  and watched Anacor’s boron-based therapeutics advance into clinical testing for acne, and a multi-year BARDA grant awarded to GSK and Anacor to develop antibacterials against bioterrorism microorganisms like Y. pestis.

6. Obesity, Diabetes, and IBS – Drugs for metabolic disorders have been well-represented in Haystack coverage since 2010. Both Carmen and See Arr Oh explored the vagaries of Zafgen’s ZGN-433 structure, as the Contrave failure threatened to sink obesity drug development around the industry. Diabetes drugs tackled some novel mechanisms and moved a lot of therapies forward, such as Pfizer’s SGLT2 inhibitors, and Takeda’s pancreatic GPCR agonist. Ironwood and Forest, meanwhile, scored an NDA for their macrocyclic peptide drug, linaclotide.

7. The Medicine Show: Pharma’s Creativity Conundrum – In this piece from October, after Steve Jobs’ passing, Forbes columnist Matt Herper both eulogizes Jobs and confronts a real ideological break between computer designers and drug developers. His emphasis? In biology and medical fields, “magical thinking” does not always fix situations as it might in computer development.

We hope you’ve enjoyed wading through the dense forest of drug development with Carmen, Aaron, Lisa, and See Arr Oh this past year. We here at The Haystack wish you a prosperous and healthy 2012, and we invite you to come back for more posts in the New Year!

From Blog: The Haystack

Takeda’s Diabetes Drug Candidate TAK-875 In Phase III Trials

Takeda Pharmaceutical today announced it has begun Phase III clinical trials of TAK-875, a first-in-class drug candidate for treating type 2 diabetes. The experimental therapy activates GPR40, a G-protein-coupled receptor that resides in pacreatic islet cells.

The TAK-875 story is as much about the biology of the target as it is about the molecule itself. And it’s a story that owes much to the company’s willingness to delve into uncharted territory.

In the early 2000s, scientists knew GPR40 existed, but didn’t know what GPR40′s purpose was in the body. Plenty of proteins fit this description– they’re called “orphan receptors” in the industry parlance. Much of Takeda’s drug discovery strategy is based on figuring out what orphan receptors do.

In a 2003 paper in Nature (DOI: 10.1038/nature01478), Takeda laid out what it learned about GPR40. The receptor responds to a variety of long-chain fatty acids. In response to fatty acid binding, GPR40 activates and boosts insulin secretion from pancreatic beta cells.

GPR40 became a viable drug target for Takeda for several reasons. First, one of the hallmarks of type 2 diabetes is a reduction in insulin secretion from pancreatic beta cells, something GPR40 activation could help counter. Second, G-protein-coupled receptors are established drug targets– and GPR40 happens to be in the class of GPCRs for which researchers know the most about structure– the Class A, or rhodopsin-like, GPCRs. (Note: other GPR-type receptors are diabetes targets as well– C&EN contributing editor Aaron Rowe has written about Arena Pharmaceuticals’ activators of GPR119 as diabetes drug candidates.)

TAK-875 docked to a model of GPR40 (ACS Med. Chem. Lett.)

Takeda used structural knowledge to its advantage in the discovery of TAK-875 (ACS Med. Chem. Lett., DOI: 10.1021/ml1000855). Researchers were able to build a model of GPR40 based on its similarity to GPCRs of known structure, and dock potential drug candidates inside to see how well they could bind.

This is far from the only drug discovery story that has to do with “de-orphanizing” orphan receptors. In fact, as far back as 1997, pharmaceutical company researchers were writing about orphan receptors as a neglected drug discovery opportunity (Trends Pharmacol. Sci., DOI: 10.1016/S0165-6147(97)90676-3). And of course, just because researchers have “de-orphanized” a receptor doesn’t mean all of the complex biology is pinned down. Case in point: the PPAR receptors (J. Med. Chem., DOI: 10.1021/jm990554g). Despite these receptors’ promise as targets for obesity and diabetes, drugs designed to target them have tanked in development or had unexpected problems after arrival on the market (read: Avandia).

So as TAK-875 enters Phase III trials, the news might be about the drug candidate’s clinical performance, but you can be sure that Takeda’s researchers are still working hard to unravel as much of GPR40′s basic biology as they can behind the scenes.

From Blog: The Haystack

Structures May Not Solve Everything

This week’s C&EN cover story is about how X-ray crystal structures of G-protein coupled receptors (GPCRs) help the hunt for new drugs. GPCRs are already a major target for drugs (if not the most popular drug target), but until recently, researchers knew little about the finer points of their structures.

As I mentioned in that story, those high-resolution protein pictures aren’t a panacea, and they won’t replace established drug-discovery technology so much as complement it. I didn’t have room to flesh out that idea in print, so I’m posting a few researchers’ thoughts on this area here today.

Some scientists thought that GPCR X-ray structures are so far of limited utility for discovering allosteric drugs, a class of GPCR-targeted drugs that can dial activity up or down rather than turning it on or off. Some GPCR-targeted drugs on the market already work this way, such as the HIV medication Maraviroc, and many more are in development. (As an aside, I feel as though every time I attend an ACS meeting talk about GPCRs, the room is packed).

“It’s the chicken and the egg story,” says Robert Lutjens, head of core biology at Addex Pharmaceuticals, which specializes in GPCR drug discovery. To get an X-ray structure of an allosteric molecule binding to a GPCR, which would be useful for developing virtual screens, one would first need to find just the right allosteric molecule—one that stabilizes the GPCR sufficiently to enable it to be crystallized. That’s difficult to do, so powerful biological assays are still critical for finding molecules that act at allosteric sites, Lutjens says. Continue reading →

From Blog: The Haystack

How Do You Get From Picture to Pill?

Just about every time C&EN covers a newly-solved structure of a G-protein coupled receptor, we throw in a sentence about how the structure has big implications for drug discovery. And rightly so- G-protein coupled receptors (GPCRs) are one of the top types of proteins targeted by drugs. But just what does that statement mean? It’s not like a medicinal chemist can look at that structure and instantly come up with a drug that controls the protein and treats a disease.

I’m in Taos, New Mexico, at a Keystone Symposium called “Transmembrane Signaling by GPCRs and Channels”, where I’m talking to researchers who take the information from pretty pictures of membrane-spanning proteins and use it to build viable drug candidates. Take a look at the Keystone Symposium’s program, and you’ll see a handful of speakers from industry. For instance, I’ve already heard a talk from Fiona Hamilton Marshall at Heptares Therapeutics and today (Wednesday) I will hear one from Kenneth E. Carlson at Anchor Therapeutics.

I’ve also had the pleasure of meeting two folks who I’ve only spotted before on Twitter- Peter Nollert (@reducentropy) of Emerald Biosystems and UCSF postdoc Ryan G. Coleman (@rgcjk).

This conference is already giving me more information than I can handle about solving GPCR structures- start drinking from the firehose with this overview of the tricks of the trade.

From Blog: The Haystack

A List I Wish Were Longer

GPCR structure, ©2007 Science

What you’re admiring is a molecular view of a G-protein coupled receptor, or GPCR for short. These receptor proteins transmit all kinds of messages in the body, in response to things as diverse as odors and neurotransmitters, and they are one of the biggest (if not the biggest) classes of drug targets. The target of blockbuster blood thinner Plavix? A GPCR. Serotonin receptors, which come up everywhere from obesity research to schizophrenia research? They’re GPCR’s. (Read some of what we’ve written about GPCR’s at the Haystack). So far, it’s been extremely tough to determine what these proteins look like, which makes it that much harder to develop drugs that could manipulate their activities.

Researchers know that GPCR’s span cell membranes, snaking back and forth across them a total of seven times. But sometimes it’s the subtle details of structure that are important for understanding how they work. Protein structures are published quite frequently, but on the rare occasion when a GPCR structure is solved, it’s a big deal. Today Ph.D. biochemist Mary Canady (@Comprendia), founder of bioscience consulting group Comprendia, tweeted this list of the GPCR structures that have been determined so far, which she obtained via Peter Nollert at Emerald BioStructures (@reducentropy). I wish the list were longer.

Bonus pre-Friday happy hour info: Canady is tweeting from the Allosteric Modulator Drug Discovery Congress, where she is picking up tidbits galore about GPCR’s. If you want to know more about allosteric modulation (anything from what it is to what kinds of drugs are in the pipeline), read my backgrounder from last year. It mentions the Rolling Stones, valium, and alcohol. What’s not to like?

From Blog: The Haystack

Addex Dishes About J&J Deal

Merck wasn’t the only company holding an R&D Day today- Swiss pharmaceutical firm Addex Pharmaceuticals also held a briefing for investors and journalists. (I didn’t get to go to Geneva, but I did watch the webcast and downloaded the presentations here.)

Addex has dedicated its entire pipeline to allosteric modulators- drug candidates that work at protein sites other than the ones where the body’s chemicals typically bind. Last fall we wrote about Addex’s strategy and its potential usefulness in tackling G-protein coupled receptors (GPCRs), one of the biggest (if not the biggest) classes of drug targets.

Today Addex updated attendees on a few different drug candidates. But the biggest news was that it disclosed the terms of its schizophrenia drug partnership with Ortho-McNeil-Janssen Pharmaceuticals, a unit of Johnson & Johnson. According to the terms of the deal, Addex could get as much as 112 million euros subject to successful completion of development and regulatory milestones. In addition, Addex is eligible for low double-digit royalties on sales of the possible schizophrenia drug it discovered, subject to regulatory approval and successful commercial launch. Addex’s stock jumped up 8.75% on the news, to 13.05 Swiss francs (about $11.75)

In the deal, Ortho gets to fund and perform preclinical and clinical development for Addex’s potential schizophrenia drug, known as ADX71149. The molecule dials up the activity of a GPCR that responds to glutamate, called mGluR2. The dialing-up part is what’s thought to be important. It’s the whole point of taking an allosteric approach. Instead of just turning a receptor on or off, you adjust its activity to acceptable levels. The philosophy at Addex is that this more subtle approach will restore more normal glutamate signaling in schizophrenia patients, with fewer of the kinds of side effects that result from an all-or-nothing, on-or-off approach. Of course all that remains to be seen for ADX71149. Phase II clinical trials (which can give an indication of therapeutic potential) for the molecule are slated to start later this year.

This nuanced approach to disease was clearly attractive to J&J, but it’s also one that many, including Addex, have stumbled over. Last December, Addex had a big disappointment when they had to stop development of their lead drug candidate, ADX10059, because of safety concerns. The molecule was in clinical trials for migraine and heartburn associated with gastroesophageal reflux disease. But a safety monitoring turned up signs of liver abnormalities in people receiving ADX10059.

From Blog: The Haystack

Liveblogging 1st Disclosures of Drug Candidates

UPDATE April 2: If you read this coverage please tell us what you thought about it here or in the comments.

1:26:15 PM: I’m @ Moscone Ctr in San Fran. T minus half hour to unveiling of new drug candidate structures. #acsmedi #acs_sf

1:37:35 PM: A hearty welcome to any readers of Totally Synthetic @Totsyn #acsmedi

2:01:50 PM: 1st: Albert J. Robichaud-of Lundbeck-on Pfizer’s $PFE SAM-531, 5-HT6 antagonist for schizophrenia, Alzheimer’s #acsmedi #acs_sf

2:02:53 PM: Alzheimer’s therapies today- palliative. Modulate eiether acetylcholine, glutamate #acsmedi #acs_sf

2:04:58 PM: ~45 million ppl with ALzheimer’s worldwide- patients have probs w learning,memory, reasoning #acsmedi #acs_sf

2:06:33 PM: 5HT6- 1 of 14 serotonin receptors- a G-protein coupled receptor #acsmedi #acs_sf

2:07:00 PM: block 5HT6- boosts levels of glutamate, acetylcholine neurotransmission in brain areas assoc w/learning, memory #acsmedi #acs_sf

2:09:37 PM: focus has been indole, azaindoles #acsmedi #acs_sf

2:09:47 PM: http://twitpic.com/1a3b3v – Lead

2:12:17 PM: SAR: aryl sulfonyl groups req’d for activity. Most substitution not good on indole NH. #acswmedi #acs_sf

2:15:13 PM: http://twitpic.com/1a3c9x – 531

2:16:59 PM: SAM-531 enhances memory retention in rodents in a test called novel object recognition #acsmedi #acs_sf

2:18:46 PM: SAM-531 potent selective 5HT6 antagonist. In phase II clinical development in patients with Alzheimer’s #acsmedi #acs_sf

2:21:00 PM: Q&A: what is brain to plasma ratio? speaker says less than 25%. But high enough for efficacy

2:22:20 PM: pKa of the amine in metabolites? HERG inhibition? pKa wasn’t known. No issues with HERG.

2:22:37 PM: Next: Thomas Simpson of AstraZeneca $AZN on AZD2624, NK3 receptor antagonist to test NK3 hypothesis in schizophrenia #acsmedi #acs_sf

2:22:46 PM: Astrazeneca on Twitter @AstraZenecaUS

2:23:22 PM: Schizophrenia: 2.2 million people in US have it #acsmedi #acs_sf

2:23:43 PM: Schiz. drugs (many are dopamine receptor antagonists) aren’t equally effective @ treating all symptoms #acsmedi #acs_sf

2:24:49 PM: NK3 blockers adjust dopamine levels by indirect mechanism- new opportunities #acsmedi #acs_sf

2:25:41 PM: Phase II studies on osanetant and talnetant- NK3r blockers- precedents in clinic #acsmedi #acs_sf

2:27:24 PM: both osenetant and talnetant are no longer in development- but support idea of NK3 #acsmedi #acs_sf

2:28:50 PM: Talnetant is a more druglike structure than osanetant #acsmedi #acs_sf

2:29:55 PM: Improve solubility and plasma protein binding of talnetant. A poster later today will outline early chem strategy. #acsmedi #acs_sf

2:32:32 PM: http://twitpic.com/1a3g8v – T

2:33:19 PM: http://twitpic.com/1a3gfd – O

2:33:42 PM: Patnent #s WO2006130080, 137789, WO200703528 #acsmedi, #acs_sf

2:35:44 PM: Sulfonate ester – this path leads to clinical candidate #acsmedi #acs_sf stability was an issue-hydrolysis

2:37:31 PM: http://twitpic.com/1a3hcu – Sulf es

2:38:49 PM: Alkylsulfonylamino groups- dramatic improvement in stability #acsmedi #acs_sf

2:39:52 PM: 2624- gerbil brain/plasma: 0.21 #acsmedi #acs_sf

2:40:12 PM: http://twitpic.com/1a3hyj – 2624

2:43:40 PM: Comparing a sulfoxide, AZD9122: half life (h): 2.8 rat, 6.7 dog. 2624 is better: 3.2 rat, 9.something in dog #acsmedi #acs_sf

2:45:22 PM: in monkeys: AZD2624 affect dopamine release measured by PET. Sulfoxide wasn’t as good in preclinical safety as 2624. #acsmedi #acs_sf

2:48:53 PM: Phase I clinical trials: 2624 is well tolerated in healthy ppl. testosterone reduction but no major adverse effects #acsmedi #acs_sf

2:50:37 PM: AZD2624 appears 2 cause testosterone reduction thru action @ hypothalamus #acsmedi #acs_sf

2:52:45 PM: Phase IIa trial: patients w schizophrenia:placebo,olanzapine,2624. #acsmedi #acs_sf

2:53:13 PM: 2624 failed to show efficacy @ dose just below what would cause testosterone fx #acsmedi #acs_sf

2:56:20 PM: $AZN has exited schizophrenia but 2624 may provide patient benefit via modulating neuroendocrine system #acsmedi #acs_sf

2:57:04 PM: other posters and talks in this area – MEDI-222, MEDI223, MEDI230, MEDI564 #acsmedi #acs_sf

3:00:07 PM: Q&A: PET study on patients too- ensure drug gets 2brain? A:was considered. but we know it gets to hypothal. #acsmedi #acs_sf

3:00:21 PM: Now-David Augeri Lexicon Pharmaceuticals $LXRX on LX2931, LX2932, S1P lyase inhibs for autoimmune disorders #acsmedi #acs_sf

3:00:33 PM: Lexicon on twitter @lexpharma

3:01:17 PM: Sphingosine-1-Phosphate (S1P)=important signaling ligand for human immune system #acsmedi #acs_sf

3:02:52 PM: S1P Lyase enzyme degrades S1P, downstream decrease in inflammatory response, fewer white blood cells in circulation #acsmedi #acs_sf

3:04:44 PM: Lexicon’s Genome 5000 Program:mouse w/out S1P lyase has fewer white blood cells in circ. they’re retained in thymus. #acsmedi #acs_sf $LXRX

3:06:23 PM: Starting point: food coloring compound THI- trace component of caramel color -has similar effect to KO of S1P lyase #acsmedi #acs_sf

3:08:56 PM: http://twitpic.com/1a3ofm – T

3:09:32 PM: Optimizing 3 areas of THI: poly-OH sidechain, imidazole core, C2 ketone #acsmedi #acs_sf

3:10:03 PM: Classic chem: team uses Amadori rearrangement and Buchi condensation to make THI analogs #acsmedi #acs_sf

3:12:06 PM: J Med Chem 2009, 52, 3941 – more on Amadori, Buchi #acsmedi #acs_sf

3:13:34 PM: http://twitpic.com/1a3pfs – No act

3:14:27 PM: Changes to core and hydroxyls not beneficial overall- C2 oxime- increased activity dramatically #acsmedi #acs_sf

3:15:38 PM: THI ketone: poor soluble as base. reactive under mild conditions-dimerizes. Oxime- potent, soluble, ez2 formulate, stable. #acsmedi #acs_sf

3:16:10 PM: Oxime is LX2931 #acsmedi #acs_sf

3:17:41 PM: How unique is 2931 activity? Tie up in heterocycle? Isoxazole-oxime isostere? #acsmedi #acs_sf

3:17:48 PM: http://twitpic.com/1a3qbg – 2931

3:19:49 PM: C2 oxazole and pyridine, no activity. isoxazole=LX2932- backup to 2931 #acsmedi #acs_sf

3:22:15 PM: http://twitpic.com/1a3r98 – 2

3:23:57 PM: LX2931Low doses work well in aggressive animal model – collagen induced arthritis #acsmedi #acs_sf

3:26:14 PM: Phase 1a trial: dose dependent decrease in lymphocyte (white blood cell) levels in patients #acsmedi #acs_sf -same as rodents, monkeys

3:27:23 PM: LX2931 is currently in Phase II clinical trials.- in patients with rheumatoid arthritis #acsmedi #acs_sf

3:30:53 PM: Q&A: what is the mechanism? direct effect on lyase? A:pursuing studies to nail down mechanism more fully

3:31:08 PM: Now Merck’s Paul Coleman shares the story of MK-4305, orexin receptor antagonist for treating insomnia #acsmedi #acs_sf

3:32:49 PM: Imsomnia: periodically affects 50% of adults #acsmedi #acs_sf

3:33:11 PM: most sleeping pills on market (eg Ambien Lunesta) adjust activity of GABA receptors #acsmedi #acs_sf

3:33:54 PM: But GABA–targetd compounds aren’t specific. FDA has issued warns:for allergy,behavior chgs,abnormal thinking #acsmedi #acs_sf

3:34:23 PM: Goal- provide restorative “natural” sleep, improve tolerability #acsmedi #acs_sf

3:35:14 PM: orexins=peptides in hypothalamus. orexin receptor=GPCR, connected to brain regions involved in wakefulness #acsmedi #acs_sf

3:37:35 PM: Actelion- clinical proof of concept with almorexant- targets orexin receptors #acsmedi #acs_sf

3:39:40 PM: PK is key- quick onset for sleep- but want the compound decaying at ~8hrs so no residuals on wakeup #acsmedi #acs_sf

3:41:12 PM: selected Assays: radioligand binding assay. Functional assay w/ calcium FLIPR , metabolite studies (important!) Pgp efflux,

3:41:51 PM: tetrahydroisoquinolines, proline amides, diazaspirodecanes among screening hits #acsmedi #acs_sf

3:42:11 PM: Two classes Merck followed up on from screens: http://bit.ly/cNyEo9 http://bit.ly/9Goj1p #acsmedi #acs_sf

3:42:25 PM: Focus is on the diazepanes #acsmedi #acs_sf

3:43:29 PM: Hit: 150nM at OX1, 3nM OX2. #acsmedi #acs_sf

3:44:09 PM: http://twitpic.com/1a3w7s – Hit

3:44:29 PM: Best heterocycle on eastern half- triazole #acsmedi #acs_sf methyl group- goes to 2.0nM, 0.6nM

3:46:17 PM: http://twitpic.com/1a3wpd – Lead

3:46:19 PM: lead=compound 9. #acsmedi #acs_sf cmpd9 doesn’t have great PK. , but demonstrated effects on orexin receptors.

3:47:39 PM: Conformational analysis of 9:low energy twist-boat structure. stab’d by pi-pi interaction #acsmedi #acs_sf Xray confirms

3:48:41 PM: PK of 9: oral bioavail less than 5% in rat. Radiolabel 9 for further studies #acsmedi #acs_sf

3:50:14 PM: metabolism-block sites of oxidation. stratgies- bridge- BMCL in press. or substituted diazepanes #acsmedi #acs_sf

3:52:54 PM: F on quinazoline wasn’t entirely beneficial- bioactivation. #acsmedi #acs_sf

3:56:10 PM: http://twitpic.com/1a3yul – 4305

3:57:14 PM: Gold standard EEG studies in rat with MK-4305- mouse implanted with EEG transmitter- what sleep stage is rat in? #acsmedi #acs_sf

3:57:51 PM: MK-4305 promotes sleep in rats dose-dependently. #acsmedi #acs_sf

3:59:22 PM: No clinical data was disclosed for MK-4305 #acsmedi #acs_sf

3:59:42 PM: MK-4305 is in Phase III clinical trials for treatment of insomnia. #acsmedi #acs_sf

4:01:39 PM: Q&A: any signs of cataplexy, side effects? A: cataplexy-loss of muscle tone as in narcolepsy, no sign of it #acsmedi #acs_sf

4:03:17 PM: In case you’re wondering, the 1st disclosures session has been packed throughout. #acsmedi #acs_sf

4:03:29 PM: Next up-BMS’s Paul Scola w/BMS-650032, NS3 protease inhibitor for Hepatitis C $BMY #acsmedi #acs_sf

4:03:47 PM: BMS on twitter – @bmsnews

4:05:36 PM: Hep C affects 3% of the world’s population, 10K deaths/yr #acsmedi #acs_sf

4:06:16 PM: HepC is leading cause of liver transplants. Virus lives in liver cells #acsmedi #acs_sf

4:06:53 PM: Today we treat HepC w/ribavirin and interferon. Nonspecific.Not equally effective for all patients. side fx-flulike symps #acsmedi #acs_sf

4:07:35 PM: $BMY – treatment will req a combo of agents. They are looking @ a # of targets #acsmedi #acs_sf

4:08:12 PM: NS3=serine protease. essential for viral replication #acsmedi #acs_sf

4:09:22 PM: BMS $BMY signature element=acylsulfonamide #acsmedi #acs_sf

4:10:18 PM: Acylsulfonamides preserve acidity of carboxylic acid at key pocket- near active site #acsmedi #acs_sf

4:10:47 PM: cyclopropylacylsulfonamide- most potent #acsmedi #acs_sf

4:12:17 PM: 781= early lead. develop SAR at various subsites. #acsmedi #acs_sf

4:12:19 PM: http://twitpic.com/1a42j5 – 781

4:14:28 PM: Small changes: change northern part of molecule to isoquinoline->inprovements in PK and liver levels #acsmedi #acs_sf

4:16:21 PM: put substitutents on isoquinoline- further improvements. ->BMS-605339 #acsmedi #acs_sf

4:17:45 PM: http://twitpic.com/1a43sx – 605339

4:17:55 PM: 605339- sustained liver levels after oral dosing to rats, dogs. levels in spleen, heart similar to plasma #acsmedi #acs_sf

4:18:38 PM: Animal models suggested a suitable safety window for 605339 #acsmedi #acs_sf

4:19:44 PM: Clinical data 605339: ECG changes caused $BMY to terminate study. Mild bradycardia #acsmedi #acs_sf

4:20:57 PM: ECG- electrocardiogram. bradycardia- slowing of the heart rate #acsmedi #acs_sf

4:22:11 PM: Next-gen compounds ID’d via isolated rabbit heart model that recaps ECG events in lab #acsmedi #acs_sf

4:23:42 PM: small changes to isoquinoline:minimize cardiovas effects. Focused on 6,6 fused heterocycles. #acsmedi #acs_sf

4:27:00 PM: I’ve twted the change to the isoquinoline in 605339- full structure soon #acsmedi #acs_sf

4:27:16 PM: http://twitpic.com/1a45zh – 605339

4:29:09 PM: 650032:potent antiviral activity after single doses. safety profile good. #acsmedi #acs_sf

4:32:31 PM: Last talk: John K. Walker from $PFE on S1P receptor agonist for treating rheumatoid arthritis #acsmedi #acs_sf

4:33:09 PM: Rheumatoid arthritis(RA)=autoimmune disease. Affects 2.1million Americans #acsmedi #acs_sf

4:33:52 PM: RA meds=mostly biologics. Expense, effectiveness vary. #acsmedi #acs_sf

4:34:47 PM: Recall from $LXRX @lexpharma talk; (S1P)=important signaling ligand for immune system #acsmedi #acs_sf

4:36:41 PM: Novartis’ fingolimod, targets S1P1- in Phase III trials for m.sclerosis- http://bit.ly/17rfX #CENews #acsmedi #acs_sf

4:36:51 PM: Fingolimod isn’t selective-hits S1P3 in heart tissues-can slow heart rate #acsmedi #acs_sf

4:38:54 PM: Starting point: 2005 report from Merck #acsmedi #acs_sf

4:40:30 PM: http://twitpic.com/1a493s – Start

4:41:47 PM: Team examined wide range of compounds to see what was needed for reducing lymphocytes in circulation #acsmedi #acs_sf

4:43:19 PM: aminocyclobutane was optimum- cis better than trans #acsmedi #acs_sf

4:45:38 PM: 591= lead #acsmedi #acs_sf. further modifications to “tail” at west end of molecule #acsmedi #acs_sf

4:47:30 PM: http://twitpic.com/1a4asd -

4:49:22 PM: endgame- success-add alpha methyl next to “a” ring #acsmedi #acs_sf

4:50:46 PM: 991- rat PK and lymphopenia data- improved PK parameters- T1/2 = 5.2hrs #acsmedi #acs_sf

4:50:55 PM: http://twitpic.com/1a4bl5 – 991

4:51:25 PM: 991 was advanced to Phase I clinical trials at beginning of last year #acsmedi #acs_sf

4:51:47 PM: full name- PF-991 #acsmedi #acs_sf

4:53:13 PM: CORRECTION to 4:27:16- that picture is of a portion of BMS-650032. NOT 605339. #acsmedi #acs_sf

4:59:22 PM: That’s it! Thanks everyone for following along. I’ll double check on BMS-650032 struc.&get it to you ASAP. #acsmedi #acs_sf

5:12:51 PM: Got the structure of BMS-650032 coming up #acsmedi #acs_sf

5:14:28 PM: http://twitpic.com/1a4h0q – 650032

5:16:33 PM: @samjlord @egonwillighagen thx for the help- i’m still learning here. geotagging sounds fascinating