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Biased Diversity for Effective Virtual Screening
No full textVirtual screening is no longer merely a matter of identifying the pool of compounds from a large collection that are active against a particular endpoint. This article shares our viewpoint as practitioners of virtual screening at Novartis, where virtual screening has evolved to a workflow combining multiple computational tools aimed at identifying quality compounds that inform drug discovery
Transforming Computed Energy Landscapes into Experimental Realities - the Role of Structural Rugosity
No full textWe exploit the possible link between structural surface roughness and difficulty of crystallisation. Polymorphs with smooth surfaces may nucleate and crystallise easier than polymorphs with rough surfaces. The concept is applied to crystal structure prediction landscapes and reveals a promising complementary way of ranking putative crystal structures
Toward a Scalable Synthesis and Process for EMA401. Part I: Late Stage Process Development, Route Scouting and ICH M7 Assessment
No full textWe present the enantioselective synthesis of sodium (3S)-5-(benzyloxy)-2-(diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (EMA401, olodanrigan), an angiotensin II type 2 antagonist. The manuscript features the process optimizations of the end game used for late phase clinical supplies; an overview of synthetic strategies identified in a route scouting exercise to a key intermediate phenylalanine derivative; and the analytical control strategy of the potentially formed highly toxic impurity bis(chloromethyl)ether (BCME). Starting from the phenylalanine derivative, we describe the optimizations of the end game from early phase to late phase processes, with consequent improvements in the PMI factor. This sequence includes a Pictet-Spengler cyclization and an amide coupling as the last bond-forming steps, and the manufacturing process was successfully implemented on a 175 kg scale in a pilot plant setup. The modified process conditions eliminated one step by in situ activation of the carboxylic acid, avoided the REACH listed solvent DMF, and resulted in a PMI improvement by a factor of 3. In the final crystallization, a new, thermodynamically more stable, modification of the drug substance was found in the complex solid-state landscape of EMA401 during an extensive polymorph screening. A process suitable for large-scale production was developed to prepare the new polymorph, avoiding the need of any special equipment such as fluidized-bed drying required in the early phase process. In the second section, some of the synthetic approaches investigated for the route scouting of the phenylalanine derivative key intermediate are presented. To conclude, we discuss the analytical control strategy for BCME, the formation of which, due to the simultaneous presence of HCl and CH2O in the Pictet-Spengler cyclization, could not be ruled out. The BCME purge factor calculations using the tools of ICH M7 control option 4 are compared to actual results from spiking experiments
The present and future of project management in pharmaceutical R&D
No full textThis is an editorial, therefore no abstrac
Transmission Electron Microscopy of the Retina: A Method for Sample Preparation and Evaluation
No full textUltrastructural pathology is critical in the morphologic evaluation and characterization of subcellular structures in nonclinical toxicity and efficacy studies. In murine models of ophthalmologic disease, clinical examination is typically paired with other techniques like electroretinography (ERG) and/or optical coherence tomography (OCT) to more fully characterize a finding. High-quality transmission electron microscopy (TEM) can provide a critical, image-based link between these approaches, providing greater confidence in interpretation of ERG or OCT results. In addition to characterization of disease models, TEM can provide detailed visualization of retinal changes identified by clinical examination or light microscopy in nonclinical toxicity studies. The spherical shape of the eye presents unique challenges for trimming, orientation, imaging, and evaluation by TEM. The varied components of the eye require specialized approaches for embedding to facilitate successful sectioning. Controlling for the orientation of the retina is critical to consistent evaluation, driving the need for an improved method of embedding this unique and complex organ. The authors describe a method of sample preparation resulting in optimal orientation of the posterior aspect of murine eyes (rat and mouse) for TEM of the neural retina, Bruch’s membrane and/or choroid, with examples from mouse ophthalmic disease models
A New Therapeutic Approach Using a Calcilytic (AXT914) for Postsurgical Hypoparathyroidism in Female Rats
No full textPostsurgical hypoparathyroidism is the most common complication of thyroid surgery. Conventional therapy with high-dose calcium and vitamin D can correct hypocalcemia but can increase the risk of hypercalciuria, renal stones, or ectopic calcification. The aim of the present study was to investigate the efficacy of a calcium-sensing receptor antagonist, also called a calcilytic (AXT914), in rat models of postsurgical hypoparathyroidism. Two postsurgical hypoparathyroidism rat models were made by hemi-parathyroidectomy or total parathyroidectomy with autotransplantation in 10-week-old female Wistar rats. AXT914 or vehicle was administered orally for 2 to 3 weeks. Serum PTH, calcium, and phosphorus levels, and the urinary excretion of calcium were measured. Autotransplanted parathyroid tissues were collected and examined histologically. In the hemi-parathyroidectomy model, the oral administration of the calcilytic AXT914 (5 and 10 mg/kg) for 2 weeks increased serum PTH and calcium levels and decreased serum phosphorus levels and urinary calcium excretion. In the total parathyroidectomy with autotransplantation model, the oral administration of AXT914 (10 mg/kg) for 3 weeks increased serum PTH and calcium levels and decreased serum phosphorus levels. The serum PTH and calcium levels increased by AXT914 were maintained for 1 week, even after discontinuation of the drug. In conclusion, AXT914 increased PTH secretion in rat models of postsurgical hypoparathyroidism, thereby correcting abnormal calcium and phosphorus homeostasis. Furthermore, AXT914 improved the functional recovery of autotransplanted parathyroid tissues
Editorial for “Echo Time-Dependence of Observed Lung T1 in Patients With Cystic Fibrosis and Correlation With Clinical Metrics”
No full textNo abstrac
Rivastigmine in Parkinson's Disease Dementia with Orthostatic Hypotension
No full textObjective: The purpose of this study was to evaluate if the cognitive benefit of rivastigmine is affected by the presence of orthostatic hypotension (OH) in patients with Parkinson's disease dementia (PDD). Methods: We conducted a post hoc analysis on 1,047 patients with PDD from 2 randomized controlled trials comparing rivastigmine versus placebo at week 24 (n = 501) and rivastigmine patch versus capsule at week 76 (n = 546). A drop ≥ 20 mm Hg in systolic blood pressure (SBP) or ≥ 10 in diastolic blood pressure (DBP) upon standing classified subjects as OH positive (OH+); otherwise, OH negative (OH-). The primary end point was the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) at week 24 and the Mattis Dementia Rating Scale (MDRS) at week 76, using intention-to-treat with retrieved dropout at week 24 and observed cases at week 76, consistent with the original analyses. Results: Overall safety was comparable between OH+ (n = 288, 27.5%) and OH- (n = 730, 69.7%), except for higher frequency of syncope (9.2%) in the OH+ placebo arm. The placebo-adjusted effect of rivastigmine on ADAS-Cog at week 24 was 5.6 ± 1.2 for OH+ and 1.9 ± 0.9 in OH- (p = 0.0165). Among subjects with OH, the MDRS change from baseline at week 76 was higher for rivastigmine capsules versus patch (10.6 ± 2.9 vs -1.5 ± 3.0, p = 0.031). The overall prevalence of OH was lower for rivastigmine than placebo at week 24 (28.3% vs 44.6%, p = 0.0476). Interpretation: The cognitive benefit from rivastigmine is larger in patients with PDD with OH, possibly mediated by a direct antihypotensive effect
Evolution of Novartis' Small Molecule Screening Deck Design
No full textThis article summarizes the evolution of the screening deck at the Novartis Institutes for BioMedical Research (NIBR). Historically, the screening deck was an assembly of all available compounds. In 2015, we designed a first deck to facilitate access to diverse subsets with optimized properties. We allocated the compounds as plated subsets on a 2D grid with property based ranking in one dimension and increasing structural redundancy in the other. The learnings from the 2015 screening deck were applied to the design of a next generation in 2019. We found that using traditional leadlikeness criteria (mainly MW, clogP) reduces the hit rates of attractive chemical starting points in subset screening. Consequently, the 2019 deck relies on solubility and permeability to select preferred compounds. The 2019 design also uses NIBR's experimental assay data and inferred biological activity profiles in addition to structural diversity to define redundancy across the compound sets