Michael Dennis Lowe
Pfizer
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Publication
Featured researches published by Michael Dennis Lowe.
Journal of Medicinal Chemistry | 2012
Neelu Kaila; Adrian Huang; Alessandro Moretto; Bruce C. Follows; Kristin Janz; Michael Dennis Lowe; Jennifer R. Thomason; Tarek S. Mansour; Cedric Hubeau; Karen Page; Paul Morgan; Susan Fish; Xin Xu; Cara Williams; Eddine Saiah
New classes of CRTH2 antagonists, the pyridazine linker containing indole acetic acids, are described. The initial hit 1 had good potency but poor permeability, metabolic stability, and PK. Initial optimization led to compounds of type 2 with low oxidative metabolism but poor oral bioavailability. Poor permeability was identified as a liability for these compounds. Addition of a linker between the indole and diazine moieties afforded a series with good potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. 32 was identified as the development track candidate. It was potent in cell based, binding, and whole blood assays and exhibited good PK profile. It was efficacious in mouse models of contact hypersensitivity (1 mg/kg b.i.d.) and house dust (20 mg/kg q.d.) when dosed orally. In sheep asthma, administration at 1 mg/kg iv completely blocked the LAR and AHR and attenuated the EAR phase.
Journal of Medicinal Chemistry | 2014
Neelu Kaila; Bruce C. Follows; Louis Leung; Jennifer R. Thomason; Adrian Huang; Alessandro Moretto; Kristin Janz; Michael Dennis Lowe; Tarek S. Mansour; Cedric Hubeau; Karen Page; Paul Morgan; Susan Fish; Xin Xu; Cara Williams; Eddine Saiah
Previously we reported the discovery of CRA-898 (1), a diazine indole acetic acid containing CRTH2 antagonist. This compound had good in vitro and in vivo potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. However, it showed low oral exposure in nonrodent safety species (dogs and monkeys). In the current paper, we wish to report our efforts to understand and improve the poor PK in nonrodents and development of a new isoquinolinone subseries that led to identification of a new development candidate, CRA-680 (44). This compound was efficacious in both a house dust mouse model of allergic lung inflammation (40 mg/kg qd) as well as a guinea pig allergen challenge model of lung inflammation (20 mg/kg bid).
Journal of Medicinal Chemistry | 2010
Adrian Huang; Alessandro Moretto; Kristin Janz; Michael Dennis Lowe; Patricia W. Bedard; Steve Tam; Li Di; Valerie Clerin; Natalia Sushkova; Boris Tchernychev; Desiree H.H. Tsao; James C. Keith; Gray Shaw; Robert G. Schaub; Qin Wang; Neelu Kaila
Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin inhibitor. It is active in a variety of animal models of cardiovascular disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound with equal potency, increased solubility, and increased exposure. We expanded our structure-activity studies in this series by branching at the alpha position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis.
Journal of Medicinal Chemistry | 2017
Katherine L. Lee; Catherine M. Ambler; David R. Anderson; Brian P. Boscoe; Andrea G Bree; Joanne Brodfuehrer; Jeanne S. Chang; Chulho Choi; Seung Won Chung; Kevin J. Curran; Jacqueline E. Day; Christoph Martin Dehnhardt; Ken Dower; Susan E. Drozda; Richard K. Frisbie; Lori Krim Gavrin; Joel Adam Goldberg; Seungil Han; Martin Hegen; David Hepworth; Heidi R. Hope; Satwik Kamtekar; Iain Kilty; Arthur Lee; Lih-Ling Lin; Frank Lovering; Michael Dennis Lowe; John Paul Mathias; Heidi M Morgan; Elizabeth Murphy
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.
Archive | 2010
Bruce C. Follows; Adrian Huang; Kristin Janz; Neelu Kaila; Michael Dennis Lowe; Tarek S. Mansour; Alessandro Moretto; Eddine Saiah; Jennifer R. Thomason; Cara Williams
Archive | 2015
David R. Anderson; Mark Edward Bunnage; Kevin J. Curran; Christoph Martin Dehnhardt; Lori Krim Gavrin; Joel Adam Goldberg; Seungil Han; David Hepworth; Horng-Chih Huang; Arthur Lee; Katherine L. Lee; Frank Lovering; Michael Dennis Lowe; John Paul Mathias; Nikolaos Papaioannou; Akshay Patny; Betsy S. Pierce; Eddine Saiah; Joseph Walter Strohbach; John David Trzupek; Richard Vargas; Xiaolun Wang; Stephen W. Wright; Christoph Wolfgang Zapf
Archive | 2017
David R. Anderson; Mark Edward Bunnage; Kevin J. Curran; Christoph Martin Dehnhardt; Lori Krim Gavrin; Joel Adam Goldberg; Han Seungil; Hepworth David; Huang Horng Chih; Arthur Lee; Katherine L. Lee; Frank Lovering; Michael Dennis Lowe; Mathias John Paul; Nikolaos Papaioannou; Akshay Patny; Betsy S. Pierce; Eddine Saiah; Joseph Walter Strohbach; John David Trzupek; Richard Vargas; Wang Xiaolun; Steven Wright; Christoph Wolfgang Zapf
Archive | 2016
Christoph Wolfgang Zapf; Seungil Han; Eddine Saiah; Xiaolun Wang; David Hepworth; David R. Anderson; Mark Edward Bunnage; Kevin J. Curran; Christopher Martin Dehnhardt; Lori Krim Gavrin; Joel Adam Goldberg; Horng-Chih Huang; Arthur Lee; Katherine L. Lee; Frank Lovering; Michael Dennis Lowe; John Paul Mathias; Nikolaos Papaioannou; Akshay Patny; Joseph Walter Strohbach; John David Trzupek; Richard Vargas; Stephen Wayner Wright; Betsy S. Pierce
Archive | 2016
Kevin J. Curran; Michael Dennis Lowe; Eddine Saiah; Betsy S. Pierce; Arthur Lee; Lori Krim Gavrin; David R. Anderson; Joel Adam Goldberg; Akshay Patny; John David Trzupek
Archive | 2015
John David Trzupek; Katherine L. Lee; Mark Edward Bunnage; Seungil Han; David Hepworth; Frank Lovering; John Paul Mathias; Nikolaos Papaioannou; Joseph Walter Strohbach; Stephen W. Wright; Christoph Wolfgang Zapf; Lori Krim Gavrin; Arthur Lee; Kevin J. Curran; Christoph Martin Dehnhardt; Eddine Saiah; Joel Adam Goldberg; Xiaolun Wang; Richard Vargas; Michael Dennis Lowe; Akshay Patny