Liveblogging First-Time Disclosures From #ACSSanDiego

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.

2:30PM LX4211
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…

Company: GlaxoSmithKline
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.

Author: Carmen Drahl

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  1. Thank you for this great information, Carmen. Full structures AND interesting details, explanations – congratulations on the excellent job!

  2. Great job! I was in a parallel session to this, but followed the live-blogging from just down the hall. Would be great to also post any PK and biomarker data for these sort of things – this would make them even more valuable.

    I would strongly support CEN doing this at future meetings!