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James A Nieman,
Sajiv K Nair,
Steven E Heasley,
Brenda L Schultz,
Herbert M Zerth, Richard A Nugent,
Ke Chen,
Kevin J Stephanski,
Todd A Hopkins,
Mary L Knechtel,
Nancee L Oien,
Janet L Wieber,
Michael W Wathen
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ABSTRACT: A series of C-2 pyrroloquinoline analogs designed to improve aqueous solubility were examined for herpesvirus polymerase and antiviral activity. Several analogs were identified that maintained the antiviral activity of the previous development candidate against HCMV, HSV-1 and VZV, but with significantly improved aqueous solubility.
Bioorganic & medicinal chemistry letters 05/2010; 20(10):3039-42. · 2.65 Impact Factor
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Mauro Mileni,
Douglas S Johnson,
Zhigang Wang,
Daniel S Everdeen,
Marya Liimatta,
Brandon Pabst,
Keshab Bhattacharya, Richard A Nugent,
Satwik Kamtekar,
Benjamin F Cravatt,
Kay Ahn,
Raymond C Stevens
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ABSTRACT: The integral membrane enzyme fatty acid amide hydrolase (FAAH) hydrolyzes the endocannabinoid anandamide and related amidated signaling lipids. Genetic or pharmacological inactivation of FAAH produces analgesic, anxiolytic, and antiinflammatory phenotypes but not the undesirable side effects of direct cannabinoid receptor agonists, indicating that FAAH may be a promising therapeutic target. Structure-based inhibitor design has, however, been hampered by difficulties in expressing the human FAAH enzyme. Here, we address this problem by interconverting the active sites of rat and human FAAH using site-directed mutagenesis. The resulting humanized rat (h/r) FAAH protein exhibits the inhibitor sensitivity profiles of human FAAH but maintains the high-expression yield of the rat enzyme. We report a 2.75-A crystal structure of h/rFAAH complexed with an inhibitor, N-phenyl-4-(quinolin-3-ylmethyl)piperidine-1-carboxamide (PF-750), that shows strong preference for human FAAH. This structure offers compelling insights to explain the species selectivity of FAAH inhibitors, which should guide future drug design programs.
Proceedings of the National Academy of Sciences 10/2008; 105(35):12820-4. · 9.68 Impact Factor
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Kyunghye Ahn,
Douglas S Johnson,
Laura R Fitzgerald,
Marya Liimatta,
Andrea Arendse,
Tracy Stevenson,
Eric T Lund, Richard A Nugent,
Tyzoon K Nomanbhoy,
Jessica P Alexander,
Benjamin F Cravatt
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ABSTRACT: Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic, anti-inflammatory, anxiolytic, and antidepressant phenotypes in rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists, indicating that FAAH may represent an attractive therapeutic target for treatment of pain, inflammation, and other central nervous system disorders. However, the FAAH inhibitors reported to date lack drug-like pharmacokinetic properties and/or selectivity. Herein we describe piperidine/piperazine ureas represented by N-phenyl-4-(quinolin-3-ylmethyl)piperidine-1-carboxamide (PF-750) and N-phenyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide (PF-622) as a novel mechanistic class of FAAH inhibitors. PF-750 and PF-622 show higher in vitro potencies than previously established classes of FAAH inhibitors. Rather unexpectedly based on the high chemical stability of the urea functional group, PF-750 and PF-622 were found to inhibit FAAH in a time-dependent manner by covalently modifying the enzyme's active site serine nucleophile. Activity-based proteomic profiling revealed that PF-750 and PF-622 were completely selective for FAAH relative to other mammalian serine hydrolases. We hypothesize that this remarkable specificity derives, at least in part, from FAAH's special ability to function as a C(O)-N bond hydrolase, which distinguishes it from the vast majority of metabolic serine hydrolases in mammals that are restricted to hydrolyzing esters and/or thioesters. The piperidine/piperazine urea may thus represent a privileged chemical scaffold for the synthesis of FAAH inhibitors that display an unprecedented combination of potency and selectivity for use as potential analgesic and anxiolytic/antidepressant agents.
Biochemistry 12/2007; 46(45):13019-30. · 3.42 Impact Factor
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Jeffrey A Pfefferkorn,
Meredith L Greene, Richard A Nugent,
Rebecca J Gross,
Mark A Mitchell,
Barry C Finzel,
Melissa S Harris,
Peter A Wells,
John A Shelly,
Robert A Anstadt,
Robert E Kilkuskie,
Laurice A Kopta,
Francis J Schwende
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ABSTRACT: A novel series of nonnucleoside HCV NS5B polymerase inhibitors were prepared from (2Z)-2-(benzoylamino)-3-(5-phenyl-2-furyl)acrylic acid, a high throughput screening lead. SAR studies combined with structure based drug design focusing on the southern heterobiaryl region of the template led to the synthesis of several potent and orally bioavailable lead compounds. X-ray crystallography studies were also performed to understand the interaction of these inhibitors with HCV NS5B polymerase.
Bioorganic & Medicinal Chemistry Letters 06/2005; 15(10):2481-6. · 2.55 Impact Factor
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Paolo Pevarello,
Maria Gabriella Brasca,
Raffaella Amici,
Paolo Orsini,
Gabriella Traquandi,
Luca Corti,
Claudia Piutti,
Pietro Sansonna,
Manuela Villa,
Betsy S Pierce, [......],
GianPaolo Fogliatto,
Enrico Pesenti,
Wilma Pastori,
Aurelio Marsiglio,
Karen L Leach,
Paula M Clare,
Francesco Fiorentini,
Mario Varasi,
Anna Vulpetti,
Martha A Warpehoski
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ABSTRACT: Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.
Journal of Medicinal Chemistry 06/2004; 47(13):3367-80. · 5.25 Impact Factor
