Jason M. Guernon
Bristol-Myers Squibb
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Featured researches published by Jason M. Guernon.
Bioorganic & Medicinal Chemistry Letters | 2011
Kenneth M. Boy; Jason M. Guernon; Jianliang Shi; Jeremy H. Toyn; Jere E. Meredith; Donna M. Barten; Catherine R. Burton; Charles F. Albright; Jovita Marcinkeviciene; Andrew C. Good; Andrew J. Tebben; Jodi K. Muckelbauer; Daniel M. Camac; Kimberley A. Lentz; Joanne J. Bronson; Richard E. Olson; John E. Macor; Lorin A. Thompson
The synthesis, evaluation, and structure-activity relationships of a class of γ-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of γ-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented.
Bioorganic & Medicinal Chemistry Letters | 2011
Lorin A. Thompson; Jianliang Shi; Carl P. Decicco; Andrew J. Tebben; Richard E. Olson; Kenneth M. Boy; Jason M. Guernon; Andrew Good; Ann Y. Liauw; Changsheng Zheng; Robert A. Copeland; Andrew P. Combs; George L. Trainor; Daniel M. Camac; Jodi K. Muckelbauer; Kimberley A. Lentz; James E. Grace; Catherine R. Burton; Jeremy H. Toyn; Donna M. Barten; Jovita Marcinkeviciene; Jere E. Meredith; Charles F. Albright; John E. Macor
The synthesis, evaluation, and structure-activity relationships of a set of related constrained diaminopropane inhibitors of BACE-1 are described. The full in vivo profile of an optimized inhibitor in both normal and P-gp deficient mice is compared with data generated in normal rats.
Journal of Medicinal Chemistry | 2017
Yong-Jin Wu; Jason M. Guernon; Jianliang Shi; Jonathan L. Ditta; Kevin J. Robbins; Ramkumar Rajamani; Amy Easton; Amy Newton; Clotilde Bourin; Kathleen W. Mosure; Matthew G. Soars; Ronald J. Knox; Michele Matchett; Rick L. Pieschl; Debra J. Post-Munson; Shuya Wang; James Herrington; John D. Graef; Kimberly Newberry; Linda J. Bristow; Nicholas A. Meanwell; Richard E. Olson; Lorin A. Thompson; Carolyn Diane Dzierba
By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine- and piperidine-based benzenesulfonamides as potent and selective Nav1.7 inhibitors. However, compound 24, one of the early analogs, failed to reduce phase 2 flinching in the mouse formalin test even at a dose of 100 mpk PO due to insufficient dorsal root ganglion (DRG) exposure attributed to poor membrane permeability. Two analogs with improved membrane permeability showed much increased DRG concentrations at doses of 30 mpk PO, but, confoundingly, only one of these was effective in the formalin test. More data are needed to understand the disconnect between efficacy and exposure relationships.
ACS Medicinal Chemistry Letters | 2016
Yong-Jin Wu; Jason M. Guernon; Fukang Yang; Lawrence B. Snyder; Jianliang Shi; Andrea McClure; Ramkumar Rajamani; Hyunsoo Park; Alicia Ng; Hal A. Lewis; Chiehying Chang; Dan Camac; Jeremy H. Toyn; Michael K. Ahlijanian; Charles F. Albright; John E. Macor; Lorin A. Thompson
By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose-response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimers disease.
Journal of Medicinal Chemistry | 2016
Yong-Jin Wu; Jason M. Guernon; Jianliang Shi; Mendi A. Higgins; Ramkumar Rajamani; Jodi K. Muckelbauer; Hal A. Lewis; Chiehying Chang; Dan Camac; Jeremy H. Toyn; Michael K. Ahlijanian; Charles F. Albright; John E. Macor; Lorin A. Thompson
Truncation of the S3 substituent of the biaryl aminothiazine 2, a potent BACE1 inhibitor, led to a low molecular weight aminothiazine 5 with moderate activity. Despite its moderate activity, compound 5 demonstrated significant brain Aβ reduction in rodents. The metabolic instability of 5 was overcome by the replacement of the 6-dimethylisoxazole, a metabolic soft spot, with a pyrimidine ring. Thus, truncation of the S3 substituent represents a viable approach to the discovery of orally bioavailable, brain-penetrant BACE1 inhibitors.
Bioorganic & Medicinal Chemistry Letters | 2015
Kenneth M. Boy; Jason M. Guernon; Yong-Jin Wu; Yunhui Zhang; Joe Shi; Weixu Zhai; Shirong Zhu; Samuel W. Gerritz; Jeremy H. Toyn; Jere E. Meredith; Donna M. Barten; Catherine R. Burton; Charles F. Albright; Andrew C. Good; James E. Grace; Kimberley A. Lentz; Richard E. Olson; John E. Macor; Lorin A. Thompson
The synthesis, evaluation, and structure-activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented.
Bioorganic & Medicinal Chemistry Letters | 2016
Yong-Jin Wu; Jason M. Guernon; Ramkumar Rajamani; Jeremy H. Toyn; Michael K. Ahlijanian; Charles F. Albright; Jodi K. Muckelbauer; Chiehying Chang; Dan Camac; John E. Macor; Lorin A. Thompson
This Letter describes the synthesis and structure-activity relationships of a series of furo[2,3-d][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine 2e bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3-d]thiazine can serve as a viable bioisostere of the known furo[3,4-d]thiazine.
Bioorganic & Medicinal Chemistry | 2017
Yong-Jin Wu; Jason M. Guernon; Andrea McClure; Guanglin Luo; Ramkumar Rajamani; Alicia Ng; Amy Easton; Amy Newton; Clotilde Bourin; Dawn D. Parker; Kathleen W. Mosure; Omar Barnaby; Matthew G. Soars; Ronald J. Knox; Michele Matchett; Rick L. Pieschl; James Herrington; Ping Chen; Digavalli V. Sivarao; Linda J. Bristow; Nicholas A. Meanwell; Joanne J. Bronson; Richard E. Olson; Lorin A. Thompson; Carolyn Diane Dzierba
Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons.
Journal of Organic Chemistry | 2016
Yong-Jin Wu; Jason M. Guernon; Hyunsoo Park; Lorin A. Thompson
Michael addition of thiourea to enones with subsequent intramolecular aminal ether formation provided easy access to furo[2,3-d]thiazinamines and pyrano[2,3-d][1,3]thiazin-2-amines. These amines served as versatile intermediates to a variety of beta-amyloid cleaving enzyme-1 (BACE1) inhibitors.
Bioorganic & Medicinal Chemistry Letters | 2018
Yong-Jin Wu; Jason M. Guernon; Andrea McClure; Brian Lee Venables; Ramkumar Rajamani; Kevin J. Robbins; Ronald J. Knox; Michele Matchett; Rick L. Pieschl; James Herrington; Linda J. Bristow; Nicholas A. Meanwell; Richard E. Olson; Lorin A. Thompson; Carolyn Diane Dzierba
Replacement of the piperidine ring in the lead benzenesulfonamide Nav1.7 inhibitor 1 with a weakly basic morpholine core resulted in a significant reduction in Nav1.7 inhibitory activity, but the activity was restored by shortening the linkage from methyleneoxy to oxygen. These efforts led to a series of morpholine-based aryl sulfonamides as isoform-selective Nav1.7 inhibitors. This report describes the synthesis and SAR of these analogs.