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Dive into the research topics where Jennifer Lafontaine is active.

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Featured researches published by Jennifer Lafontaine.


Experimental Eye Research | 2009

Ocular pharmacokinetics and hypotensive activity of PF-04475270, an EP4 prostaglandin agonist in preclinical models.

Ganesh Prasanna; Jay Fortner; Cathie Xiang; Eric Zhang; Samantha Carreiro; Scott Anderson; Soisurin Sartnurak; Grace Wu; Hovhannes J. Gukasyan; M.R. Niesman; Sajiv K. Nair; Eugene Rui; Jennifer Lafontaine; Chau Almaden; Peter A. Wells; A. Krauss

Prostaglandins are widely used to lower intraocular pressure (IOP) as part of the treatment regimen for glaucoma. While FP and EP2 agonists are known to lower IOP, we investigated the ocular hypotensive activity and ocular drug distribution of PF-04475270, a novel EP4 agonist following topical administration in normotensive Beagle dogs. PF-04475270 is a prodrug of CP-734432, which stimulated cAMP formation in HEK293 cells expressing EP4 receptor and beta-lactamase activity in human EP4 expressing CHO cells transfected with a cAMP response element (CRE) with an EC(50) of 1 nM. Prodrug conversion and transcorneal permeability were assessed in rabbit corneal homogenates and a human corneal epithelial cell (cHCE) model. The compound underwent rapid hydrolysis to CP-734432 in corneal homogenates, and exhibited good permeability in the cHCE model. The descending order of ocular exposure to CP-734432 after topical dosing of PF-04475270 in dogs was as follows: cornea > aqueous humor >or= iris/ciliary body. When administered q.d., PF-04475270 lowered IOP effectively in the dog IOP model both after single and multiple days of dosing. A maximum decrease in IOP with PF-04475270 was between 30 and 45% at 24h post-dose relative to that observed with vehicle. In conclusion, PF-04475270 is a novel ocular hypotensive compound which is bioavailable following topical dosing, effectively lowering IOP in dogs. EP4 agonists could be considered as potential targets for lowering IOP for the treatment of glaucoma and ocular hypertension.


Journal of Medicinal Chemistry | 2017

Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR.

Simon Paul Planken; Douglas Carl Behenna; Sajiv Krishnan Nair; Theodore Otto Johnson; Asako Nagata; Chau Almaden; Simon Bailey; T. Eric Ballard; Louise Bernier; Hengmiao Cheng; Sujin Cho-Schultz; Deepak Dalvie; Judith Gail Deal; Dac M. Dinh; Martin Paul Edwards; Rose Ann Ferre; Ketan S. Gajiwala; Michelle Hemkens; Robert Steven Kania; John Charles Kath; Jean Matthews; Brion W. Murray; Sherry Niessen; Suvi T. M. Orr; Mason Alan Pairish; Neal W. Sach; Hong Shen; Manli Shi; James Solowiej; Khanh Tran

Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.


Bioorganic & Medicinal Chemistry Letters | 2009

Synthesis and SAR of 4-substituted-2-aminopyrimidines as novel c-Jun N-terminal kinase (JNK) inhibitors.

Paul S. Humphries; Jennifer Lafontaine; Charles S. Agree; David Alexander; Ping Chen; Quyen-Quyen T. Do; Lilian Y. Li; Elizabeth A. Lunney; Ranjan Jagath Rajapakse; Karen Siegel; Sergei Timofeevski; Tianlun Wang; David M. Wilhite

The development of a series of novel 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. Optimization of microsomal clearance led to the identification of 9c, whose kinase selectivity is reported.


Bioorganic & Medicinal Chemistry Letters | 2011

Identification of novel pyrrolopyrazoles as protein kinase C β II inhibitors

Hui Li; Yufeng Hong; Seiji Nukui; Jihong Lou; Sarah Johnson; Stephanie Scales; Iriny Botrous; Eileen Valenzuela Tompkins; Chunfeng Yin; Ru Zhou; Mingying He; Jordan Jensen; Djamal Bouzida; Gordon Alton; Jennifer Lafontaine; Stephan Grant

A novel series of pyrrolopyrazole-based protein kinase C β II inhibitors has been identified from high-throughput screening. Herein, we report our initial structure-activity relationship studies with a focus on optimizing compound ligand efficiency and physicochemical properties, which has led to potent inhibitors with good cell permeability.


European Journal of Pharmacology | 2010

Discovery of a novel class of targeted kinase inhibitors that blocks protein kinase C signaling and ameliorates retinal vascular leakage in a diabetic rat model

Stephan Grant; Phong Tran; Qin Zhang; Aihua Zou; Dac M. Dinh; Jordan Jensen; Sue Zhou; Xiaolin Kang; Joseph Zachwieja; John Lippincott; Kevin K.-C. Liu; Sarah Johnson; Stephanie Scales; Chunfeng Yin; Seiji Nukui; Chad L. Stoner; Ganesh Prasanna; Jennifer Lafontaine; Peter A. Wells; Hui Li

Protein kinase C (PKC) family members such as PKCbetaII may become activated in the hyperglycemic state associated with diabetes. Preclinical and clinical data implicate aberrant PKC activity in the development of diabetic microvasculature abnormalities. Based on this potential etiological role for PKC in diabetic complications, several therapeutic PKC inhibitors have been investigated in clinical trials for the treatment of diabetic patients. In this report, we present the discovery and preclinical evaluation of a novel class of 3-amino-pyrrolo[3,4-c]pyrazole derivatives as inhibitors of PKC that are structurally distinct from the prototypical indolocarbazole and bisindolylmaleimide PKC inhibitors. From this pyrrolo-pyrazole series, several compounds were identified from biochemical assays as potent, ATP-competitive inhibitors of PKC activity with high specificity for PKC over other protein kinases. These compounds were also found to block PKC signaling activity in multiple cellular functional assays. PF-04577806, a representative from this series, inhibited PKC activity in retinal lysates from diabetic rats stimulated with phorbol myristate acetate. When orally administered, PF-04577806 showed good exposure in the retina of diabetic Long-Evans rats and ameliorated retinal vascular leakage in a streptozotocin-induced diabetic rat model. These novel PKC inhibitors represent a promising new class of targeted protein kinase inhibitors with potential as therapeutic agents for the treatment of patients with diabetic microvascular complications.


Journal of Medicinal Chemistry | 2015

Design, synthesis, and evaluation of NO-donor containing carbonic anhydrase inhibitors to lower intraocular pressure.

Qinhua Huang; Eugene Y. Rui; Morena Cobbs; Dac M. Dinh; Hovhannes J. Gukasyan; Jennifer Lafontaine; Saurabh Mehta; Brian D. Patterson; D.A. Rewolinski; Paul F. Richardson; Martin Paul Edwards

The antiglaucoma drugs dorzolamide (1) and brinzolamide (2) lower intraocular pressure (IOP) by inhibiting the carbonic anhydrase (CA) enzyme to reduce aqueous humor production. The introduction of a nitric oxide (NO) donor into the alkyl side chain of dorzolamide (1) and brinzolamide (2) has led to the discovery of NO-dorzolamide 3a and NO-brinzolamide 4a, which could lower IOP through two mechanisms: CA inhibition to decrease aqueous humor secretion (reduce inflow) and NO release to increase aqueous humor drainage (increase outflow). Compounds 3a and 4a have shown improved efficacy of lowering IOP in both rabbits and monkeys compared to brinzolamide (2).


Journal of Ocular Pharmacology and Therapeutics | 2009

In Vivo Evaluation of 11β-Hydroxysteroid Dehydrogenase Activity in the Rabbit Eye

Scott Anderson; Samantha Carreiro; Terri Quenzer; David Gale; Cathie Xiang; Hovhannes J. Gukasyan; Jennifer Lafontaine; Hengmiao Cheng; Achim H.-P. Krauss; Ganesh Prasanna

PURPOSE Steroids are used in a diverse range of conditions in clinical ophthalmology and one of the most significant complications is corticosteroid-induced glaucoma, which is characterized by an increase in intraocular pressure (IOP). 11beta-Hydroxysteroid dehydrogenase-1 (11beta-HSD1) is known to catalyze the interconversion of hormonally inactive cortisone to hormonally active cortisol and is widely expressed in the eye, particularly ciliary epithelium. Carbenoxolone (CBX), an 11beta-HSD1 inhibitor, has been shown to reduce IOP in healthy volunteers and patients with ocular hypertension (OHT). The purpose of this study was to: (1) develop an in vivo model for the assessment of cortisone to cortisol conversion in the eye, that is, 11beta-HSD1 activity and (2) assess the pharmacokinetic/pharmacodynamic relationship following topical treatment with 11beta-HSD1 inhibitors using an in vivo rabbit model. METHODS Potent and selective 11beta-HSD1 inhibitors were topically administered to the rabbit eye and exogenous cortisone to endogenous cortisol conversion in the eye was assessed in rabbits. Tissues were then evaluated for cortisone, cortisol, and 11beta-HSD1 inhibitor levels by LC/MS/MS. Concomitantly cortisol activity in ocular tissue samples was determined using a secondary mechanistic pLuc-GRE assay. RESULTS Topical treatment with potent and selective 11beta-HSD1 inhibitors resulted in complete inhibition in the conversion of cortisone to cortisol in the rabbit eye as well as decreased pLuc-GRE luciferase activity. The reduction of cortisone conversion was time- and dose-dependent as well as dependent on dosing volume (suggestive of increased spillover and washout with greater dosing volume). CONCLUSIONS In conclusion, topical delivery of 11beta-HSD1 inhibitors can reduce or inhibit the conversion of cortisone to cortisol in the eye, indicating that the rabbit eye possesses an active enzyme for glucocorticoid synthesis. Dosing concentration and volume play an important role in the pharmacokinetic and pharmacodynamic effects of topically delivering an 11beta-HSD1 inhibitor. The rabbit model is useful for mechanistically assessing the conversion of cortisone to cortisol in the eye.


Cancer Research | 2015

Abstract 2594: Characterization of a novel irreversible third generation EGFR TKI that targets T790M-mediated resistant EGFR-mutant NSCLC while sparing wild type EGFR

Mike Zientek; Sangita M. Baxi; Henry Cheng; Valeria R. Fantin; Jun Li Feng; Allison M. Given; Zelanna Goldberg; Jie Guo; Michelle Hemkens; John Charles Kath; Jennifer Lafontaine; Gary Li; Pramod P. Mehta; Brion W. Murray; Sajiv K. Nair; Simon Paul Planken; Chad Ray; Yuli Wang; Manli Shi; Anand Sistla; Tod Smeal; Greg Stevens; Wei Tan; Paolo Vicini; Marlena Walls; Liu Yang; Min-Jean Yin; Scott Weinrich

Activating mutations in EGFR confer constitutive activity providing the oncogenic drive in EGFR-mutant NSCLC. First and 2nd generation EGFR tyrosine kinase inhibitors (TKIs) are effective drugs in this setting, but are constrained by dose-limiting toxicities attributed to inhibition of wild type (WT) EGFR and by drug resistance caused, in the majority of cases, via a T790M secondary mutation in EGFR. We report the pharmacology of a novel irreversible 3rd generation EGFR TKI active against EGFR with activating and T790M mutations, but sparing WT EGFR. Our novel 3rd generation EGFR TKI was studied in a variety of in vitro and in vivo models to determine its inhibitory potencies on different EGFR variants, pharmacokinetics (PK), antitumor efficacy, exposure-response relationships, mechanism of action, and predicted human efficacious dose. In enzyme and cell assays, our compound is a highly potent inhibitor of EGFR double mutants (L858R/T790M and Del/T790M) and EGFR activating mutants (L858R and Del), but a weak inhibitor of WT EGFR (26-fold margin over mutant target potencies). Effects on downstream signaling and function indicate the underlying mechanism of the compound is direct inhibition of EGFR, with subsequent inhibition of downstream signaling that results in apoptosis and viable cell decline. In xenograft mouse models, the compound demonstrates tumor growth inhibition and regression at well-tolerated doses in models driven by EGFR double mutants and EGFR activating mutants. The antitumor efficacy is dose-dependent and strongly correlates with inhibition of EGFR phosphorylation and EGFR-mediated downstream signaling, and induction of apoptosis. Plasma concentrations assumed to be sufficient for efficacy (Ceff) were defined using a mathematical model incorporating the plasma levels of the compound, the associated inhibitory effects on EGFR phosphorylation, and the antitumor efficacy in the double and activating mutant xenograft models. Ceff was in agreement across several models and was used with in vitro human PK properties to calculate required human dose. While our compound possesses a similar profile as other recently disclosed 3rd generation EGFR TKIs, this molecule is distinguished by better potency on the activating mutants and by the widest potency margin on WT EGFR. Given that the target potencies and WT margins of 3rd generation EGFR TKIs have been sufficient for tolerated clinical efficacy in preliminary results, it can be inferred that our compound will have similar promise in the clinic. These results support our compound as a novel EGFR TKI with an inhibitory profile and favorable drug-like properties that suggest utility for treating patients with NSCLC with EGFR activating and resistance mutations. Citation Format: Mike Zientek, Sangita Baxi, Henry Cheng, Valeria Fantin, Jun Li Feng, Allison Given, Zelanna Goldberg, Jie Guo, Michelle Hemkens, John Kath, Jennifer Lafontaine, Gary Li, Pramod Mehta, Brion Murray, Sajiv Nair, Simon Planken, Chad Ray, Yuli Wang, Manli Shi, Anand Sistla, Tod Smeal, Greg Stevens, Wei Tan, Paolo Vicini, Marlena Walls, Liu Yang, Min-Jean Yin, Scott L. Weinrich. Characterization of a novel irreversible third generation EGFR TKI that targets T790M-mediated resistant EGFR-mutant NSCLC while sparing wild type EGFR. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2594. doi:10.1158/1538-7445.AM2015-2594


Archive | 2001

Alpha-aryl ethanolamines and their use as beta-3 adrenergic receptor agonists

Robert Francis Day; Jennifer Lafontaine


Archive | 2007

4-pyrimidine-5-amino-pyrazole compounds

Peng Chen; Yufeng Hong; Paul S. Humphries; Jr. Theodore Otto Johnson; Jennifer Lafontaine; Song Liu; Elizabeht Ann Lunney

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