Article pubs.acs.org/jmc † †,# Imidazolopiperazines: Lead Optimization of the Second-Generation Antimalarial Agents †,# Advait Nagle, Tao Wu, Kelli Kuhen, Kerstin Gagaring, Rachel Borboa, Caroline Francek, Zhong Chen,† David Plouﬀe,† Xuena Lin,‡ Christopher Caldwell,‡ Jared Ek,† Suzanne Skolnik,‡ Fenghua Liu,‡ Jianling Wang,‡ Jonathan Chang,† Chun Li,† Bo Liu,† Thomas Hollenbeck,† Tove Tuntland,† John Isbell,† Tiﬀany Chuan,† Philip B. Alper,† Christoph Fischli,§,∥ Reto Brun, Suresh B. Lakshminarayana,⊥ Matthias Rottmann,§,∥ Thierry T. Diagana,⊥ Elizabeth A. Winzeler, Richard Glynne,† David C. Tully,† and Arnab K. Chatterjee*,† † §,∥ † † † †Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States ‡Novartis Institute for Biomedical Research, Preclinical Proﬁling Group, Cambridge, Massachusetts §Swiss Tropical and Public Health Institute, Parasite Chemotherapy, CH-4002 Socinstrasse 57, CD-4002 Basel, Switzerland ∥University of Basel, CH-4003 Basel, Switzerland ⊥Novartis Institute for Tropical Diseases, 10 Biopolis Road, 05-01 Chromos, Singapore-138670 *S Supporting Information ABSTRACT: On the basis of the initial success of optimi- zation of a novel series of imidazolopiperazines, a second genera- tion of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the out- come of a set of in vitro metabolic identiﬁcation studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhib- ited improved potency, in vitro metabolic stability proﬁle and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more eﬃcacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve suﬃcient multiples of the oral exposure at the eﬃcacious dose in toxicology studies. ■ INTRODUCTION After decades of neglect, the search for novel, eﬀective anti- malarials has been revived primarily due to emergence of drug resistance.1 Widespread resistance has been reported not only for 8-aminoquinolines but recent reports indicate the appear- ance of increased parasite tolerance to artemisinin analogues, potentially predicating clinical resistance.2 The absence of highly eﬃcacious malaria vaccines highlights the importance of developing small-molecule drugs.3 With support from the Wellcome Trust and Medicines for Malaria Venture (MMV), the NGBS consortium (the Novartis Institute for Tropical Diseases (NITD), the Genomics Institute of the Novartis Research Foundation (GNF), the Biomedical Primate Research Centre (BPRC), and the Swiss Tropical and Public Health Institute (STPHI)) was formed and set up to discover new antimalarials which are eﬀective against multidrug resistant parasite strains. This collaboration has produced promising new leads.1a,4 Here we report our continued eﬀort to optimize a series of imidazolopiperazine compounds in search of a pre- clinical candidate. The lead compound we identiﬁed was com- pound 1.5 As described previously, an extensive SAR study on the three peripheral parts had yielded decent in vitro and in vivo antimalarial activities as well as favorable physiochemical and pharmacokinetic properties. Our eﬀorts toward the ﬁrst-generation compounds led to candidates (like compound 1) with double-digit nanomolar potency and moderate oral exposure in mice. However, most potent compounds with an unsubstituted piperazine had poor oral exposure which resulted in inferior in vivo eﬃcacy when administered orally, for example, compounds 28 and 31 (Scheme 1) in the previous communication (Figure 1).5 We were intrigued by the possibility of further reﬁning the core structure of the molecule to further improve the properties. Our hypothesis was further reinforced by chemical stability and mouse in vitro metabolic stability results which led to the identi- ﬁcation of two biologically inactive metabolites (1a and 1b) arising from the oxidation of piperazine ring. Our plan was to substitute three possible positions (positions 5, 6, and 8) to Received: January 11, 2012 Published: April 23, 2012 © 2012 American Chemical Society 4244 dx.doi.org/10.1021/jm300041e | J. Med. Chem. 2012, 55, 4244−4273