Posts Tagged → type 2 diabetes
Watch this space on Sunday as I cover the public unveiling of five drug candidates’ structures. I’ll be liveblogging the “First Disclosures of Clinical Candidates” symposium at the San Diego ACS National Meeting, which runs from 2PM to 5PM Pacific.
1:30PM It’s half an hour before the start of the session and the big ballroom is still pretty empty. Expect that to change in short order.
Company: Lexicon Pharmaceuticals
Meant to treat: type 2 diabetes
Mode of action: dual inhibitor of sodium glucose transporters 1 and 2, which play key roles in glucose absorption in the gastrointestinal tract and kidney
Medicinal chemistry tidbits: this drug candidate had Lexicon’s chemists refamiliarizing themselves with carbohydrate chemistry. Most inhibitors of sodium glucose transporters incorporate D-glucose in some way. Lexicon’s chemists realized they could try something different– inhibitors based on the scaffold of L-xylose, a non-natural sugar. The team has already published a J. Med. Chem paper (2009, 52, 6201–6204) explaining that strategy. LX4211 is a methyl thioglycoside-the team went with a methyl thioglycoside because upping the size too far beyond a methyl lost activity at SGLT1.
Status in the pipeline: LX4211 is currently completing Phase IIb trials.
Company: Bristol-Myers Squibb
Meant to treat: migraine
Mode of action: antagonist of the receptor for calcitonin gene-related peptide- increased levels of this peptide have been reported in cases of migraine
Medicinal chemistry tidbits: This team recently published an orally bioavailable CGRP inhibitor, BMS-846372 (ACS Med. Chem. Lett., DOI: 10.1021/ml300021s). However, BMS-846372 had limited aqueous solubility, something that might make its development challenging. To improve that solubility, the BMS team sought to add polar groups to their molecule, something that’s been tough to do with CGRP inhibitors historically. In the end, the team managed to add a primary amine to BMS-846372′s cycloheptane ring while maintaining CGRP activity, leading to BMS-927711.
Status in the pipeline: Phase II clinical trials
3:05 lots of questions from the audience for this talk! One questioner notes (as was noted in talk) that 4 CGRP inhibitors had gone before this drug in the clinic, and not made it through. Speaker notes that this candidate is more potent than others at CGRP (27 picomolar).
3:53 We’re a bit behind schedule but got plenty of good chemistry…
Meant to treat: tumors with loss-of-function in the tumor suppressor protein PTEN (phosphatase and tensin homolog)- 2nd most inactivated tumor suppressor after p53- cancers where this is often the case include prostate and endometrial
Mode of action: inhibitor of phosphoinositide 3-kinase-beta (PI3K-beta). Several lines of evidence suggest that proliferation in certain PTEN-deficient tumor cell lines is driven primarily by PI3K-beta.
Medicinal chemistry tidbits: The GSK team seemed boxed in because in 3 out of 4 animals used in preclinical testing, promising drug candidates had high clearance. It turned out that a carbonyl group that they thought was critical for interacting with the back pocket of the PI3K-beta enzyme wasn’t so critical after all. When they realized they could replace the carbonyl with a variety of functional groups, GSK2636771 eventually emerged. GSK2636771B (shown) is the tris salt of GSK2636771.
Status in the pipeline: Phase I clinical trials
Company: Gilead Sciences
Meant to treat: chronic infection with hepatitis B and C viruses
Mode of action: agonist of Toll-like receptor 7, which recognizes RNA from viral sources
Medicinal chemistry tidbits: The team paid a lot of attention to particular sidechain in their drug candidates– they examined a range of pKa’s from the acidic side of the scale to the basic side, and learned that a basic amine was important for agonist activity.
Status in the pipeline: Phase Ib clinical trials
Company: Bristol-Myers Squibb
Meant to treat: hepatitis C
Mode of action: inhibitor of viral NS5B replicase
Medicinal chemistry tidbits: This drug candidate is an allosteric inhibitor– early on in the program BMS researchers had evidence to suggest that allosteric inhibition of the replicase would be feasible, and would provide an alternative to the nucleoside analogs that constitute the vast majority of replicase inhibitors. The team started with fused indole lead structures which bound to the thumb site 1 allosteric site in the replicase (Bioorg. Med. Chem. Lett., DOI: 10.1016/j.bmcl.2011.03.067). Adding a morpholine amide enhanced potency, and adding substituents to it abrogated transactivation of the pregnane X receptor (PXR). Ultimately this group was replaced with a methylated piperazine, with substituents stitched together to give another ring. A cyclopropane adjusted the shape of the molecule to jibe with information gathered from an X-ray co-crystal structure.
Status in the pipeline: Phase II clinical trials
4:52 That’s it folks! Watch for additional coverage of these talks in an April issue of C&EN.
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.)
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.
1PM Pacific: There’s one hour left before chemists will pack a ballroom in Anaheim to see potential new drugs’ structures unveiled for the first time. Watch this space for updates.
2:39PM Pacific: CEP-26401
This drug candidate now has a name: irdabisant
meant to treat: deficits in cognition and/or attention in diseases such as Alzheimer’s and schizophrenia
mode of action: inverse agonist of histamine H3 receptor, which regulates several neurotransmitter pathways involved in cognition, attention, memory
medicinal chemistry tidbits: Cephalon’s goal was to bring a high quality compound to the clinic to define the utility, if any, of H3 antagonists for these indications. The team studied compounds in this area that failed. Among the things they learned was that several adverse events could be tied to drug candidates’ lipophilicity. So the team prioritized lipophilicity and other such characteristics in its discovery workflow. status in the pipeline: completing Phase I in the beginning of April 2011, advancing to Phase II
structure coming soon!
UPDATED 3/29 with structure:
3:16PM Pacific: BMS-663068
company: Bristol-Myers Squibb
meant to treat: HIV
mode of action: inhibits HIV attachment to host cells by binding to the viral envelope gp120 protein and interfering with its attachment to host CD4 receptors
medicinal chemistry tidbits: potency and getting the drug candidates to reach the bloodstream efficiently were key. Replacing a methoxy group on with heterocycles, such as triazoles, gave a big boost in potency.
status in the pipeline: Completed Phase IIa clinical trials. Phase IIb studies are planned for later this year.
meant to treat: irritable bowel syndrome
mode of action: blocks a subtype of tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis, in the gut.
medicinal chemistry tidbits: Lexicon started their medchem program with an open mind. They could have made a molecule that was exquisitely selective for the subtype of tryptophan hydroxylase in the gut, they could avoid hitting the other subtype by making their molecule stay out of the brain, or both. They ultimately ended up using the latter strategy, making molecules slightly on the heavy side (above 500 or 550 molecular weight) and adding groups like a carboxylic acid, that tend to keep things out of the brain.
status in the pipeline: Completed Phase IIa clinical trials.
5:30PM Pacific: MK-0893
meant to treat: type 2 diabetes
mode of action: blocks the receptor for the hormone glucagon. Glucagon is released by the pancreas in response to falling glucose levels.
medicinal chemistry tidbits: Merck kept several chemical scaffolds in play during this research program. But the team’s big breakthrough was adding a methyl group to the benzylic position of a promising compound, which greatly improved potency. This methyl group strategy hadn’t worked for previous compound series, but the team revisited it anyway.
status in the pipeline: Completed some Phase II trials, according to clinicaltrials.gov
meant to treat: Alzheimer’s disease
mode of action: blocks gamma-secretase, a key enzyme in the production of amyloid-beta, the peptide behind the plaques that mar Alzheimer’s patients’ brains.
medicinal chemistry tidbits: Adding a cyclopropyl group and a trifluoromethyl group enhanced molecules’ metabolic stability.
status in the pipeline: discontinued because of adverse liver side effects unrelated to its mode of action.
5:31PM Pacific: That’s all for now, folks. I hope to update with more structure information later. Watch for my full story on this symposium in a mid-April issue of C&EN.