Deuterium is Go

Concert Pharmaceuticals and GlaxoSmithKline recently announced a collaboration to develop deuterium-containing medicines, including CTP-518, a partially deuterated version of the HIV protease inhibitor, atazanavir (Reyataz™), marketed by Bristol-Myers Squibb. Reyataz™ is used in combination therapy to treat HIV/AIDS and, for most patients, the recommended dose is one 300mg tablet daily taken with ritonavir (Norvir™). Ritonavir was originally developed as a ‘stand-alone’ HIV protease inhibitor but is now primarily used, not for its antiviral activity, but to ‘boost’ levels of other protease inhibitors by inhibiting their metabolism. Despite its marked benefits as part of combination therapy, ritonavir is poorly tolerated by some patients and also influences the metabolism of concurrently administered drugs, especially those metabolised by CYP 3A4.

Concert is pioneering the modification of existing medicines by selectively replacing hydrogen atoms with deuterium atoms in the expectation that the modified compounds will have similar activity at the target enzyme or receptor, together with improved ADME properties. CTP-518 has been shown to have similar antiviral potency to atazanavir but slower hepatic metabolism, leading to the hope that it could be used clinically without the need for ‘boosting’ by ritonavir. This could lead to better safety and tolerability for patients and also allow for the inclusion of CTP-518 in fixed dose regimens. CTP-518 is expected to enter Phase I clinical trials in the second half of 2009.

Concert has filed a patent application (WO20081566632) claiming derivatives of atazanavir, including compounds 120 and 122.
Deuterated atazanavir
The antiviral activities of compounds 120 and 122 were shown to be similar to, or slightly better than, that of atazanavir, both in the presence and absence of serum proteins. In human liver microsomes, compounds 120 and 122 showed an approximately 50% increase in half life compared with atazanavir. Following oral co-dosing in rats, compound 122 showed a 43% increase in half life, a 67% increase in Cmax and an 81% increase in AUC compared with atazanavir. When administered to chimps, both compounds showed around 50% increases in half life compared with atazanavir and about 2-fold increases in urine concentration.

Exploiting the Kinetic Isotope Effect in Drug Discovery

kinetic isotope effectThe Kinetic Isotope Effect (KIE) refers to the dependence of rate of reaction on the isotopic identity of an atom participating in the reaction. The largest effect is observed when the isotopic replacement is made to an atom involved in bond breaking or formation in the rate-limiting step – a primary isotope effect. When the isotopic substitution is made to an atom that does not participate in the rate-determining step, the magnitude of the effect is smaller – a secondary isotope effect. This property has long been used in the elucidation of reaction mechanisms.

The KIE is most pronounced when the relative mass change of the substituted isotope is large. For example, a change from hydrogen to deuterium represents a 100% increase in mass, whilst a 12C to 13C change represents only an 8% increase. Reactions involving C-H bonds are typically 6-10 times faster than the corresponding C-D bonds, whereas a reaction involving 12C is only marginally faster than the corresponding 13C reaction.

In addition to its utility in elucidation of reaction mechanisms, deuterium has also found application as a non-radioactive isotopic tracer for studying metabolic pathways. Because of the KIE, however, care has to be taken that the substitution does not modify metabolism. Turning this property to advantage, two US companies are targeting deuterated versions of clinically proven drugs to identify analogues with improved properties.

venlafaxineIn October 2008, Auspex Pharmaceuticals announced positive results from its Phase 1 clinical trial of SD-254, claiming the first validation in humans of targeted deuterium substitution. SD-254 is a deuterium substituted version of venlafaxine, a selective serotonin-norepinephrine reuptake inhibitor (SNRI). The trial indicated a superior pharmacokinetic profile for SD-254 compared to venlafaxine.

paroxetineAt around the same time, Concert Pharmaceuticals reported preclinical data on CTP-347, a deuterium substituted version of the selective serotonin reuptake inhibitor (SSRI), paroxetine. CTP-347 is being developed to treat vasomotor symptoms (hot flashes) caused by tamoxifen treatment or the menopause. CTP-347 does not cause mechanism-based inactivation of CYP2D6 at clinically relevant concentrations and may be more suitable for co-administration with tamoxifen which is activated by metabolism by CYP2D6. CTP-347 is currently in Phase I clinical testing.

Both companies have numerous other deuterated compounds in their pipelines targeting a wide range of therapeutic indications.