Brian A. McKittrick

History and Prospects of Drug Discovery and Development Collaboration between Industry and Academia

Sheo Bux Singh, Gary E. Martin, Brian A. McKittrick, Jonathan M. Crowther et autres

Research collaborations and licensing deals are critical for the discovery and development of life-saving drugs. This practice has been ongoing since the inception of the pharmaceutical industry. The current process of drug discovery and development is complex, regulated, and highly regimented, having …

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Peptide Nucleic Acids Containing Cationic/Amino-Alkyl Modified Bases Promote Enhanced Hybridization Kinetics and Thermodynamics with Single-Strand DNA

Frank Podlaski, Stephen Cornwell, Kenny K. Wong, Brian A. McKittrick et autres

Peptide nucleic acids (PNAs) are antisense molecules with excellent polynucleotide hybridization properties; they are resistant to nuclease degradation but often have poor cell permeability leading to moderate cellular activity and limited clinical results. The addition of cationic substitutions (positive charges) to PNA …

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CCDC 2018403: Experimental Crystal Structure Determination

Mihirbaran Mandal, Alexei V. Buevich, Hongwu Wang, Andrew P. J. Brunskill 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, …

Unprecedented Reversal of Regioselectivity during Methanolysis and an Interception of Curtius Rearrangement

Mihirbaran Mandal, Alexei V. Buevich, Hongwu Wang, Andrew P. J. Brunskill et autres

Abstract Unprecedented reversal in regioselectivity during methanolysis of anhydrides due to the change in substitution pattern of fluorine in the phenyl moiety, and the formation of nitrene intercepted intermediates during Curtius rearrangement of the acids were the major impediments for discovering bioactive …

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Generation of Leads for γ‑Secretase Modulation

Mihirbaran Mandal, Alexei V. Buevich, John P. Caldwell, Lynn A. Hyde et autres

Abstract Herein, we disclose three structurally differentiated γ-secretase modulators (GSMs) based on an oxadiazine scaffold. The analogues from series I potently inhibit the generation of Aβ42 in vitro when the substituents at 3 and 4 positions of the oxadiazine moiety adopt an …

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FERRY: access control and quota management service

Mine Altunay, Joseph Boyd, Bruno Coimbra, Kenneth Richard Herner et autres

Fermilab developed the Frontier Experiments RegistRY (FERRY) service that provides a centralized repository for access control and job management attributes such as batch and storage access policies, quotas, batch priorities and NIS attributes for cluster configuration. This paper describes the FERRY architecture, …

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Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates

Mihirbaran Mandal, Yusheng Wu, Jeffrey Misiaszek, Guoqing Li et autres

We describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 …

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Iminopyrimidinones: A novel pharmacophore for the development of orally active renin inhibitors

Brian A. McKittrick, John P. Caldwell, Thomas A. Bara, George C. Boykow et autres

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Discovery of potent iminoheterocycle BACE1 inhibitors

John P. Caldwell, Robert Mazzola, James Durkin, Joseph Chen et autres

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Biased Ligand Modulation of Seven Transmembrane Receptors (7TMRs): Functional Implications for Drug Discovery

Craig C. Correll, Brian A. McKittrick

Seven transmembrane receptors (7TMRs), also known as G-protein-coupled receptors (GPCRs), have proven to be valuable targets for the development of therapeutics. The expansion of our understanding of 7TMR downstream signaling pathways beyond G-proteins has broadened our appreciation of the versatility of these …

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Identification of 2-aminooxazole amides as acyl-CoA: Diacylglycerol acyltransferase 1 (DGAT1) inhibitors through scaffold hopping strategy

Hyunjin M. Kim, Michelle D. Smith, Jae‐Hun Kim, Mary Ann Caplen et autres

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Design and Validation of Bicyclic Iminopyrimidinones As Beta Amyloid Cleaving Enzyme-1 (BACE1) Inhibitors: Conformational Constraint to Favor a Bioactive Conformation

Mihirbaran Mandal, Zhaoning Zhu, Jared N. Cumming, Xiaoxiang Liu et autres

On the basis of our observation that the biaryl substituent of iminopyrimidinone 7 must be in a pseudoaxial conformation to occupy the contiguous S1-S3 subsites of BACE1, we have designed a novel fused bicyclic iminopyrimidinone scaffold intended to favor this bioactive conformation. …

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