Powered by Open Innovation: Opportunities and Challenges in the Pharma Sector.

The value of innovation in medicines is clear. Despite all of the progress in the twenty-first century, there are still many unmet medical needs and opportunities to improve healthcare. The challenges for pharmaceutical companies include ways in which to stay competitive and flexible in an environment of constant knowledge growth and increasingly sophisticated technologies, and ways to generate sufficient revenues to sustain their own growth. To that end, pharmaceutical companies are compelled to adapt different business models in the face of new challenges. The industry is plagued with long research and development (R&D) cycles and low success rates for innovative treatments; something has to change. The need to collaborate externally across the process of discovery, development, manufacturing and commercialization is a must. Furthermore, collaborations have increased in frequency and scope, expanding the opportunities to access global scientific talent in academia, research institutes and biotechnology companies. Despite the perception that pharma companies are 'closed' or tightly controlled industries, open innovation is already well established in the pharmaceutical sector and used to supplement R&D in the process of bringing new medicines for patients faster, and at a lower cost. Over the years, each pharma company has tailored the open-innovation concept to develop its own model based on particular needs and offerings. Independently of the model, the creation of successful partnerships in external innovation requires reaching out and connecting beyond the traditional organizational boundaries. Substantial internal cultural changes are required to implement open-innovation strategies that should co-exist without competing with the traditional ways of operating. Major changes bring challenges but create multiple opportunities for scientists and organizations. High-quality drug discovery requires continuous learning and an open way of thinking to adopt novel operational models and to implement efficient collaborations.

Open Innovation Drug Discovery (OIDD): a potential path to novel therapeutic chemical space.

The continued development of computational and synthetic methods has enabled the enumeration or preparation of a nearly endless universe of chemical structures. Nevertheless, the ability of this chemical universe to deliver small molecules that can both modulate biological targets and have drug-like physicochemical properties continues to be a topic of interest to the pharmaceutical industry and academic researchers alike. The chemical space described by public, commercial, in-house and virtual compound collections has been interrogated by multiple approaches including biochemical, cellular and virtual screening, diversity analysis, and in-silico profiling. However, current drugs and known chemical probes derived from these efforts are contained within a remarkably small volume of the predicted chemical space. Access to more diverse classes of chemical scaffolds that maintain the properties relevant for drug discovery is certainly needed to meet the increasing demands for pharmaceutical innovation. The Lilly Open Innovation Drug Discovery platform (OIDD) was designed to tackle barriers to innovation through the identification of novel molecules active in relevant disease biology models. In this article we will discuss several computational approaches towards describing novel, biologically active, drug-like chemical space and illustrate how the OIDD program may facilitate access to previously untapped molecules that may aid in the search for innovative pharmaceuticals.

Structure-activity relationships of the antimalarial agent artemisinin. 7. Direct modification of (+)-artemisinin and in vivo antimalarial screening of new, potential preclinical antimalarial candidates.

On the basis of earlier reported quantitative structure-activity relationship studies, a series of 9beta-16-(arylalkyl)-10-deoxoartemisinins were proposed for synthesis. Several of the new compounds 7 and 10-14 were synthesized employing the key synthetic intermediate 23. In a second approach, the natural product (+)-artemisinic acid was utilized as an acceptor for conjugate addition, and the resultant homologated acids were subjected to singlet oxygenation and acid treatment to provide artemisinin analogues. Under a new approach, we developed a one step reaction for the interconversion of artemisinin 1 into artemisitene 22 that did not employ selenium-based reagents and found that 2-arylethyliodides would undergo facile radical-induced conjugate addition to the exomethylene lactone of 22 in good yield. The lactone carbonyls were removed sequentially by diisobutylaluminum hydride reduction followed directly by a second reduction (BF(3)-etherate/Et(3)SiH) to afford the desired corresponding pyrans. Six additional halogen-substituted aromatic side chains were installed via 22 furnishing the bioassay candidates 15-20. The analogues were examined for in vitro antimalarial activity in the W-2 and D-6 clones of Plasmodium falciparum and were additionally tested in vivo in Plasmodium berghei- and/or Plasmodium yoelii-infected mice. Several of the compounds emerged as highly potent orally active candidates without obvious toxicity. Of these, two were chosen for pharmacokinetic evaluation, 14 and 17.

Structure-activity relationships of the antimalarial agent artemisinin. 6. The development of predictive in vitro potency models using CoMFA and HQSAR methodologies.

Artemisinin (1) is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua L. Because of the effectiveness of Artemisinin in the treatment of drug-resistant Plasmodium falciparum and its rapid clearance of cerebral malaria, development of clinically useful semisynthetic drugs for severe and complicated malaria (artemether, artesunate) was prompt. However, recent reports of fatal neurotoxicity in animals with dihydroartemisinin derivatives such as artemether have spawned a renewed effort to develop nontoxic analogues of artemisinin. In our effort to develop more potent, less neurotoxic agents for the oral treatment of drug-resistant malaria, we utilized comparative molecular field analysis (CoMFA) and hologram QSAR (HQSAR), beginning with a series of 211 artemisinin analogues with known in vitro antimalarial activity. CoMFA models were based on two conformational hypotheses: (a) that the X-ray structure of artemisinin represents the bioactive shape of the molecule or (b) that the hemin-docked conformation is the bioactive form of the drug. In addition, we examined the effect of inclusion or exclusion of racemates in the partial least squares (pls) analysis. Databases derived from the original 211 were split into chiral (n = 157), achiral (n = 34), and mixed databases (n = 191) after leaving out a test set of 20 compounds. HQSAR and CoMFA models were compared in terms of their potential to generate robust QSAR models. The r(2) and q(2) (cross-validated r(2)) were used to assess the statistical quality of our models. Another statistical parameter, the ratio of the standard error to the activity range (s/AR), was also generated. CoMFA and HQSAR models were developed having statistically excellent properties, which also possessed good predictive ability for test set compounds. The best model was obtained when racemates were excluded from QSAR analysis. Thus, CoMFA of the n = 157 database gave excellent predictions with outstanding statistical properties. HQSAR did an outstanding job in statistical analysis and also handled predictions well.