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.
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.
The 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.
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