Article pubs.acs.org/jmc
Carbamoyl Pyridone HIV‑1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744) Brian A. Johns,*,† Takashi Kawasuji,‡ Jason G. Weatherhead,† Teruhiko Taishi,‡ David P. Temelkoff,† Hiroshi Yoshida,‡ Toshiyuki Akiyama,‡ Yoshiyuki Taoda,‡ Hitoshi Murai,‡ Ryuichi Kiyama,‡ Masahiro Fuji,‡ Norihiko Tanimoto,‡ Jerry Jeffrey,† Scott A. Foster,† Tomokazu Yoshinaga,‡ Takahiro Seki,‡ Masanori Kobayashi,‡ Akihiko Sato,‡ Matthew N. Johnson,† Edward P. Garvey,† and Tamio Fujiwara‡ †
GlaxoSmithKline Research & Development, Infectious Diseases Therapeutic Area Unit, Five Moore Drive, Research Triangle Park, North Carolina 27709, United States ‡ Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka-shi, Osaka 561-0825, Japan S Supporting Information *
ABSTRACT: We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure−activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clinical development.
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INTRODUCTION
HIV/AIDS remains a serious threat to public health worldwide. The latest UNAIDS report for the end of 2012 indicates the number of people living with HIV worldwide now resides at over 34 million.1 This number has stabilized or grown slightly over the past few years, but unfortunately there are still approximately 2.5 million new infections annually and 1.7 million deaths. Antiretroviral (ARV) drugs have been one of the major advancements in medicine over the past 25 years and have turned HIV/AIDS into a manageable chronic disease. One notable recent development is the realization of HIV integrase inhibitors (INIs) as a new class of approved drugs. HIV-1 integrase (IN) is a virally encoded enzyme that catalyzes two biochemical reactions and is essential for replication. First, it catalyzes the removal of the terminal two nucleotides on the respective 3′ ends of the viral DNA (termed 3′ processing). Second, IN facilitates the nicking of host chromosomal DNA by the newly exposed 3′ hydroxyl moieties, resulting in strand transfer of the viral dsDNA. Integrase strand transfer inhibitors (INSTi’s) have become an attractive drug target over the past few years, with numerous two-metal chelating scaffolds being pursued based on the pharmacophore shown in Figure 1.2 © XXXX American Chemical Society
Figure 1. Two-metal binding pharmacophore model for HIV-1 integrase strand transfer inhibitors.
Two examples of metal-binding INSTi’s are raltegravir (RAL, 1) and elvitegravir (EVG, 2), which received regulatory approval in 2007 and 2012, respectively (Figure 2). While these are both impressive new antiretrovirals and have established INSTi’s as Received: May 1, 2013
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dx.doi.org/10.1021/jm400645w | J. Med. Chem. XXXX, XXX, XXX−XXX
Journal of Medicinal Chemistry
Article
moiety required for potent inhibition of the integration strand transfer event. A key feature of this novel carbamoyl pyridone motif was the intentional use of a triad of all oxygen-derived lone pairs to serve as the chelating donor atoms toward the two divalent metals. This concept was derived from the hard/soft acid/base theory in order to match the harder oxygen atoms in the carbamoyl pyridone motif with the hard metal properties of the divalent magnesium cofactor. It was our hypothesis that previous scaffolds suffered from the less-than-optimal affinity of a borderline nitrogen lone pair for the hard Mg2+ cofactors, potentially leading to a less favorable and/or selective inhibition of the HIV-1 integrase catalytic activity. Cohen has recently shown a pyrone core to have superior inhibitory activity in an integrase biochemical assay when compared to several related scaffolds in a systematic study of a set of core heterocylic motifs.12 The conclusions from his work about the importance of hard Lewis base donor character of the inhibitor are completely consistent with our hypotheses and findings from the current study and our previous work. The Cohen study has also suggested the relative orientation of one 5- and one 6- membered metalocyclic ring to the two magnesium ion positions was important. It is noteworthy that in the case of our system, the 5- and 6-membered rings formed upon metal coordination are reversed relative to the pyrone system studied due to the different positioning of the benzyl carboxamide.13 While monocyclic analogues were potent, further enhancement of the structure was necessary to improve the resistance profile. Additionally, modification of the 2-ester substituent to the corresponding series of amides resulted in significant losses in activity, thus limiting the ability to optimize these small yet attractive structures. This ester to amide potency decrease was attributed to conformational barriers preventing the amide group from existing in a coplanar arrangement with the pyridone motif, thus preventing an optimal coordination of both Mg2+ simultaneously. The series evolved into bicyclic derivatives represented by structure 6. The conformational challenges were relieved by this change and potency against wild-type (wt) virus restored, but key resistant mutations were still problematic. However, when the bicyclic system was further substituted with a hydroxyl moiety on the saturated piperazinone ring (e.g., 7) significant improvements in the potency against a key integrase position 148 mutant (Q148K) were observed. Additionally, the addition of human serum (HS) to the antiviral assay to mimic the physiological environment resulted in only a modest decrease in activity. However, control of the new hydroxyl group’s stereochemistry present in 7 during synthesis and its subsequent configurational integrity were problematic. We envisioned that a solution to the stability concerns of the hydroxyl group would be to tether it into a tricyclic system as in 8.
Figure 2. HIV-1 integrase strand transfer inhibitors.
valued components for combination antiretroviral therapy, they both have distinct limitations and leave room for meaningful improvements for patients. Raltegravir is the first-in-class INSTi but requires a high dose of 400 mg twice daily (BID).3 In addition, three major IN signature mutation pathways result in substantial loss of potency of RAL (N155H, Y143C, and Q148H(R)(K)) and render it ineffective against these viruses.4,5 EVG treatment engenders slightly different resistance pathways (T66I, E92Q, S147G, Q148H(R)(K), N155H), but there is extensive EVG cross resistance among RAL failures.6 The major advance that EVG provides is the option for once daily dosing (QD). However, this requires the use of a pharmacokinetic (PK) boosting agent such as ritonavir or cobicistat to inhibit CYP3A4, which is a primary route of metabolism for EVG.7 As a result of these limitations, our primary objective was to find a medicine that would allow once-daily doses (
