Francis A. Mennona
Hoffmann-La Roche
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Featured researches published by Francis A. Mennona.
Journal of Medicinal Chemistry | 1989
Robert William Guthrie; Gerald Lewis Kaplan; Francis A. Mennona; Jefferson Wright Tilley; Richard W. Kierstead; Margaret O'Donnell; Herman J. Crowley; Bohdan Yaremko; Ann F. Welton
A series of N-[4-(3-pyridinyl)butyl]-5,5-disubstituted-pentadienamides was prepared and evaluated for PAF-antagonist activity. Compounds were assayed in vitro in a PAF-binding assay employing washed, whole dog platelets as the receptor source and in vivo after intravenous or oral administration for their ability to prevent PAF-induced bronchoconstriction in guinea pigs. Criteria required for good oral activity in the latter model include an (E,-E)-5-phenyl-2,4-pentadienamide, a second phenyl or a four- or five-carbon alkyl moiety in the 5-position of the diene, and an (R)-[1-alkyl-4-(3-pyridinyl)butyl] substituent on the carboxamide nitrogen atom. The alkyl substituent on this side chain can be methyl, ethyl, or cyclopropyl. Two members of this series, [R-(E)]-5,5-bis(4-methoxy-phenyl)-N- [1-methyl-4-(3-pyridinyl)butyl]- 2,4-pentadienamide (31) and [R-(E,E)]-5-(4-methoxyphenyl)-N-[1-methyl-4- (3-pyridinyl)butyl]-2,4-decadienamide (58), were selected for further pharmacological evaluation. Both were found to be substantially longer acting after oral administration than the corresponding S enantiomers in the guinea pig bronchoconstriction assay. A second in vivo model used to evaluate PAF antagonists determines the ability of test compounds to decrease the area of skin wheals induced by an intradermal injection of PAF. In this model, using both rats and guinea pigs, compounds 31 and 58 were found to be as active as the reference PAF antagonist 3-[4-(2-chlorophenyl)-9-methyl-6H- 1-(4-morpholinyl)-1-propanone (45).
Bioorganic & Medicinal Chemistry Letters | 2000
Li Chen; Jefferson Wright Tilley; Robert William Guthrie; Francis A. Mennona; Tai-Nan Huang; Gerry Kaplan; Richard Trilles; Dorota Miklowski; Nicolas Huby; Virginia Schwinge; Barry A. Wolitzky; Karen Rowan
A series of N-(N-benzylpyroglutamyl)-4-substituted-L-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. Analogues substituted by electron deficient benzoylamino groups bearing bulky ortho substituents had low-nM potency in an ELISA assay and low-microM activity in a cell based assay.
Bioorganic & Medicinal Chemistry Letters | 2008
Shawn David Erickson; Bruce L. Banner; Steven Joseph Berthel; Karin Conde-Knape; Fiorenza Falcioni; Irina Hakimi; Bernard Michael Hennessy; Robert Francis Kester; Kyungjin Kim; Chun Ma; Warren William Mccomas; Francis A. Mennona; Steven Gregory Mischke; Lucy Orzechowski; Yimin Qian; Hamid Salari; John P. Tengi; Kshitij Chhabilbhai Thakkar; Rebecca Taub; Jefferson Wright Tilley; Hong Wang
This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.
ACS Medicinal Chemistry Letters | 2013
Yimin Qian; Wendy Lea Corbett; Steven Joseph Berthel; Duk Soon Choi; Mark T. Dvorozniak; Wanping Geng; Paul Gillespie; Kevin Richard Guertin; Nancy-Ellen Haynes; Robert Francis Kester; Francis A. Mennona; David Moore; Jagdish Kumar Racha; Roumen Nikolaev Radinov; Ramakanth Sarabu; Nathan Robert Scott; Joseph Grimsby; Navita L. Mallalieu
To resolve the metabolite redox cycling associated with our earlier clinical compound 2, we carried out lead optimization of lead molecule 1. Compound 4 showed improved lipophilic ligand efficiency and demonstrated robust glucose lowering in diet-induced obese mice without a liability in predictive preclinical drug safety studies. Thus, it was selected as a clinical candidate and further studied in type 2 diabetic patients. Clinical data suggests no evidence of metabolite cycling, which is consistent with the preclinical profiling of metabolism.
Journal of Medicinal Chemistry | 1983
Richard W. Kierstead; Faraone A; Francis A. Mennona; Mullin J; Robert William Guthrie; Herman J. Crowley; Simko B; Blaber Lc
Archive | 2003
Shaoqing Chen; Wendy Lea Corbett; Kevin Richard Guertin; Nancy-Ellen Haynes; Robert Francis Kester; Francis A. Mennona; Steven Gregory Mischke; Yimin Qian; Ramakanth Sarabu; Nathan Robert Scott; Kshitij Chhabilbhai Thakkar
Archive | 2003
Shaoqing Chen; Wendy Lea Corbett; Kevin Richard Guertin; Nancy-Ellen Haynes; Robert Francis Kester; Francis A. Mennona; Steven Gregory Mischke; Yimin Qian; Ramakanth Sarabu; Nathan Robert Scott; Kshitij Chhabilbhai Thakkar
Journal of Medicinal Chemistry | 1973
Robert William Guthrie; Alfred Boris; John Guilfoyle Mullin; Francis A. Mennona; Richard W. Kierstead
Journal of Medicinal Chemistry | 1973
Robert William Guthrie; Alfred Boris; Francis A. Mennona; John Guilfoyle Mullin; Richard W. Kierstead
Archive | 1979
Robert William Guthrie; Richard W. Kierstead; Francis A. Mennona; Ann C. Sullivan