Patrick Brassil

Lung-restricted ALK5 inhibition avoids systemic toxicities associated with TGFβ pathway inhibition

Jonathan Maher, Rui Zhang, Gopinath S. Palanisamy, Kimberly Perkins et autres

Systemic therapies targeting transforming growth factor beta (TGFβ) or TGFβR1 kinase (ALK5) have been plagued by toxicities including cardiac valvulopathy and bone physeal dysplasia in animals, posing a significant challenge for clinical development in pulmonary indications. The current work aims to demonstrate …

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Gut-Selective Design of Orally Administered Izencitinib (TD-1473) Limits Systemic Exposure and Effects of Janus Kinase Inhibition in Nonclinical Species

Rhiannon N. Hardwick, Patrick Brassil, Ilaria Badagnani, Kimberly Perkins et autres

Izencitinib (TD-1473), an oral, gut-selective pan-Janus kinase (JAK) inhibitor under investigation for treatment of inflammatory bowel diseases, was designed for optimal efficacy in the gastrointestinal tract while minimizing systemic exposures and JAK-related safety findings. The nonclinical safety of izencitinib was evaluated in …

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Pharmacokinetics of TD-8236, a Lung-Selective pan-JAK Inhibitor, Following Single-Dose Administration in Mice, Rats, and Dogs

C. Thompson, David L. Bourdet, Matthew Frates, Prof. Mrunal K Shirsat et autres

Rationale: Janus kinases (JAKs) play a central role in signaling the pro-inflammatory effects of multiple cytokines. TD-8236 is a pan-JAK inhibitor designed for delivery to the lungs for treatment of inflammatory lung conditions. By selectively retaining a targeted JAK inhibitor in the …

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Development of Gut-Selective Pan-Janus Kinase Inhibitor TD-1473 for Ulcerative Colitis: A Translational Medicine Programme

William J. Sandborn, Deanna D. Nguyen, David T. Beattie, Patrick Brassil et autres

BACKGROUND AND AIMS: Oral systemic pan-Janus kinase [JAK] inhibition is effective for ulcerative colitis [UC] but is limited by toxicities. We describe preclinical to clinical translation of TD-1473-an oral gut-selective pan-JAK inhibitor-from in vitro characterization through a Phase 1b study in patients …

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Heteroarylamide smoothened inhibitors: Discovery of N-[2,4-dimethyl-5-(1-methylimidazol-4-yl)phenyl]-4-(2-pyridylmethoxy)benzamide (AZD8542) and N-[5-(1H-imidazol-2-yl)-2,4-dimethyl-phenyl]-4-(2- pyridylmethoxy)benzamide (AZD7254)

Bin Yang, Alexander W. Hird, Michael S. Bodnarchuk, Xiaolan Zheng et autres

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Adventures in Scaffold Morphing: Discovery of Fused Ring Heterocyclic Checkpoint Kinase 1 (CHK1) Inhibitors

Bin Yang, Melissa M. Vasbinder, Alexander W. Hird, Qibin Su et autres

Checkpoint kinase 1 (CHK1) inhibitors are potential cancer therapeutics that can be utilized for enhancing the efficacy of DNA damaging agents. Multiple small molecule CHK1 inhibitors from different chemical scaffolds have been developed and evaluated in clinical trials in combination with chemotherapeutics …

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Intestinally-restricted Janus Kinase inhibition: a potential approach to maximize the therapeutic index in inflammatory bowel disease therapy

David T. Beattie, M. Teresa Pulido‐Rios, Fei Shen, Melissa Ho et autres

BACKGROUND: An unmet need remains for safe and effective treatments to induce and maintain remission in inflammatory bowel disease (IBD) patients. The Janus kinase (JAK) inhibitor, tofacitinib, has demonstrated robust efficacy in ulcerative colitis patients although, like other systemic immunosuppressants, there may …

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CCDC 1013311: Experimental Crystal Structure Determination

Gregory S. Basarab, Patrick Brassil, P. Doig, Vincent Galullo et autres

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, …

Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization

Gregory S. Basarab, Patrick Brassil, P. Doig, Vincent Galullo et autres

The compounds described herein with a spirocyclic architecture fused to a benzisoxazole ring represent a new class of antibacterial agents that operate by inhibition of DNA gyrase as corroborated in an enzyme assay and by the inhibition of precursor thymidine into DNA …

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Biotransformation and bioactivation reactions of alicyclic amines in drug molecules

Jayaprakasam Bolleddula, Kevin DeMent, James P. Driscoll, Philip Worboys et autres

Aliphatic nitrogen heterocycles such as piperazine, piperidine, pyrrolidine, morpholine, aziridine, azetidine, and azepane are well known building blocks in drug design and important core structures in approved drug therapies. These core units have been targets for metabolic attack by P450s and other …

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Structure activity relationship studies of 3-arylsulfonyl-pyrido[1,2-a]pyrimidin-4-imines as potent 5-HT6 antagonists

Shuanghua Hu, Yazhong Huang, Yong‐Jin Wu, Huan He et autres

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A novel uHPLC–MS/MS method for the quantitation of AZD7451 (AZ12607092) in human plasma

Cody J. Peer, Jeffrey L. Brown, Timothy J. Martin, Jeffrey A. Roth et autres

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