Aliphatic chlorides (!) in drug design

I’ve already shared my fascination for chlorine in drug design (https://www.dhirubhai.net/pulse/flavor-week-chlorine-gilles-ouvry/) and I was pretty content with not mentioning chlorine ever again …and then Novartis came out with Asciminib (JMedChem2018). The molecule contains an –OCF2Cl group, which I had never run into before; probably for good reason: why would someone add a chlorine to an already pretty big and lipophilic group? Looking at the 2 matched pair in the Novartis paper, it would appear that the chlorine brings more to activity than its lipophilicity (ΔLipE >0 from measured logD). 

A closer look at the pdb structure of Asciminib in ABL (5mo4) highlights a beautiful halogen bond between the chlorine and the backbone carbonyl of Leu448 which probably explains some of the boost in LipE. (for more reading on halogen bond, check out Yue Pan’s LinkedIn posts (https://www.dhirubhai.net/pulse/beyond-hydrogen-bond-halogen-chalcogen-pnicogen-yue-pan/ ).

Taking a look in the small molecule Xray world (CSD), CCDC’s IsoStar finds more than 4500 cases where a carbonyl is in contact with an aliphatic chloride. The density map (red is the most dense) highlights carbonyls on chlorine-carbon axis perfectly positioned for a halogen bond. It’s interesting to see that this atom brings more then just size and lipophilicity. It offers the possibility to make additional (probably not terribly strong, but additional) interactions with different type of residues (carbonyls (halogen bond or Dunitz like), hydrogen bond donors, thioethers and aromatics). A quick look in the PDB confirms this with a couple of nice examples including some Cl->H-N and Cl->C(O).

Pushing this idea a bit further, the OCF2Cl group (kinked, out of plane like -OCF3) could be seen as a bioisostere of a -CH2SO2NH2. 

I was not able to find any examples out there but in theory it could mimick the interactions while massively modifying properties. (By the way, I am not suggesting as a general thing to do but just in that rare case where your molecule already has 3 sulphonamides, negative logD and you need to get in the brain…this could be a thing to try).

So, what other aliphatic chlorides could be potential used in drug design (not counting reactive chlorines for covalent inhibitors)? If you take into account chemical reactivity (SN1, SN2) and chemical stability, the number of candidates dwindles down pretty quickly. In fact, I’ve only come up with a two other interesting substituent: -CF2Cl on an aromatic and chloro cyclopropyls. Unfortunately, there are only very limited examples in the literature of these groups. 

One notable exception comes from Roche scientists in their HepC NS5B program (JMedChem2013). In this case, they were looking for tertBu replacements and synthesised (amongst others) a chloro cyclopropyl substituent. Activity is maintained with the desired increased metabolic stability (I guess nothing much can happen to this group now). Unfortunately, no other data is given as they ended up going for another substituent. 

Additional logD data on this group can be found in the Bayer agrochemical literature (it turns out that you can find tables and tables of measured logDs in agrochemical patents)

With this in mind, Cl-cPr should be added to the ever growing list of tertBu replacements ( for one of many reviews, see ChemMedChem2015) with more than one option to gain additional interactions with the protein.

#drug #drugdiscovery #medicinal #medicinalchemistry #Drug Hunter #CSD