California Dreaming of Macrocycles
When I go to a 'first disclosure' talk, where drug candidates' structures are publicly revealed for the first time, I try to do my homework in advance. But there are always a few surprises. Take the candidate unveiled at the ACS meeting by Paul M. Scola of Bristol Myers-Squibb. BMS-650032 is a potential Hepatitis C treatment. It inhibits a protease that's essential for the hepatitis C virus's replication. I'd learned from the team's abstract that BMS had already advanced another compound (BMS-605339) to clinical trials, and that that compound was discontinued because of some mild adverse findings. So I tried to figure out what parts of BMS-605339 the team might've adjusted to resolve those effects.
I thought I'd found a clue in a recent patent from the BMS team (WO/2009/140500). They patented compounds that contained a large ring, a macrocycle.
This got my attention for a few reasons. Two years ago, we covered the disclosure of Merck's MK-7009, another potential treatment for hepatitis C that blocks the same protease. MK-7009 contains a macrocycle.
Also, macrocycles, when applied strategically, can be beneficial in drug discovery, enhancing metabolic stability or binding affinity for a given drug target, as Scola and a few other experts told us last year.
"It's got to be a macrocycle," I thought. Well, I thought wrong. BMS-650032 doesn't contain a macrocycle, after all- the only modifications that the team made to the original clinical candidate, BMS-605339, to arrive at 650032 were very subtle substituent changes to an isoquinoline ring. But the team did indeed examine macrocycles, Scola told me in San Francisco.