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Ian M Bell,
Craig A Stump, Steven N Gallicchio,
Donnette D Staas,
C Blair Zartman,
Eric L Moore,
Nova Sain,
Mark Urban,
Joseph G Bruno,
Amy Calamari,
Amanda L Kemmerer,
Scott D Mosser,
Christine Fandozzi,
Rebecca B White,
Matthew M Zrada,
Harold G Selnick,
Samuel L Graham,
Joseph P Vacca,
Stefanie A Kane,
Christopher A Salvatore
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ABSTRACT: Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.
Bioorganic & medicinal chemistry letters 04/2012; 22(12):3941-5. · 2.65 Impact Factor
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ABSTRACT: Identification of an HIV integrase inhibitor with micromolar affinity for the CGRP receptor led to the discovery of a series of structurally novel CGRP receptor antagonists. Optimization of this series produced compound 16, a low-molecular weight CGRP receptor antagonist with good pharmacokinetic properties in both rat and dog. In contrast to other nonpeptide antagonists, the activity of 16 was affected by the presence of divalent cations and showed evidence of an alternative, RAMP-independent CGRP receptor binding site.
Bioorganic & medicinal chemistry letters 11/2011; 21(22):6705-8. · 2.65 Impact Factor
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Christopher A Salvatore,
Eric L Moore,
Amy Calamari,
Jacquelynn J Cook,
Maria S Michener,
Stacey O'Malley,
Patricia J Miller,
Cyrille Sur,
David L Williams,
Zhizhen Zeng, [......],
Yui S Tang,
Chi-Chung Li,
Nicole T Pudvah,
Rebecca B White,
Ian M Bell, Steven N Gallicchio,
Samuel L Graham,
Harold G Selnick,
Joseph P Vacca,
Stefanie A Kane
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ABSTRACT: Calcitonin gene-related peptide (CGRP) has long been hypothesized to play a key role in migraine pathophysiology, and the advent of small-molecule antagonists has clearly demonstrated a clinical link between blocking the CGRP receptor and migraine efficacy. 2-[(8R)-8-(3,5-Difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) represents the third CGRP receptor antagonist to display clinical efficacy in migraine trials. Here, we report the pharmacological characterization of MK-3207, a potent and orally bioavailable CGRP receptor antagonist. In vitro, MK-3207 is a potent antagonist of the human and rhesus monkey CGRP receptors (K(i) = 0.024 nM). In common with other CGRP receptor antagonists, MK-3207 displays lower affinity for CGRP receptors from other species, including canine and rodent. As a consequence of species selectivity, the in vivo potency was assessed in a rhesus monkey pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging. MK-3207 produced a concentration-dependent inhibition of dermal vasodilation, with plasma concentrations of 0.8 and 7 nM required to block 50 and 90% of the blood flow increase, respectively. The tritiated analog [3H]MK-3207 was used to study the binding characteristics on the human CGRP receptor. [3H]MK-3207 displayed reversible and saturable binding (K(D) = 0.06 nM), and the off-rate was determined to be 0.012 min(-1), with a t(1/2) value of 59 min. In vitro autoradiography studies on rhesus monkey brain slices identified the highest level of binding in the cerebellum, brainstem, and meninges. Finally, as an index of central nervous system penetrability, the in vivo cerebrospinal fluid/plasma ratio was determined to be 2 to 3% in cisterna magna-ported rhesus monkeys.
Journal of Pharmacology and Experimental Therapeutics 04/2010; 333(1):152-60. · 3.83 Impact Factor
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Craig A Stump,
Ian M Bell,
Rodney A Bednar,
John F Fay, Steven N Gallicchio,
James C Hershey,
Richard Jelley,
Constantine Kreatsoulas,
Eric L Moore,
Scott D Mosser, [......],
Shane A Roller,
Christopher A Salvatore,
Steven S Sharik,
Cory R Theberge,
C Blair Zartman,
Stefanie A Kane,
Samuel L Graham,
Harold G Selnick,
Joseph P Vacca,
Theresa M Williams
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ABSTRACT: A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K(i)=23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K(i)=0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species.
Bioorganic & medicinal chemistry letters 02/2010; 20(8):2572-6. · 2.65 Impact Factor
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Ian M. Bell, Steven N. Gallicchio,
Michael R. Wood,
Amy G. Quigley,
Craig A. Stump,
C. Blair Zartman,
John F. Fay,
Chi-Chung Li,
Joseph J. Lynch,
Eric L. Moore,
Scott D. Mosser,
Thomayant Prueksaritanont,
Christopher P. Regan,
Shane Roller,
Christopher A. Salvatore,
Stefanie A. Kane,
Joseph P. Vacca,
Harold G. Selnick
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ABSTRACT: Incorporation of polar functionality into a series of highly potent calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort to improve pharmacokinetics. This strategy identified piperazinone analogues that possessed improved solubility at acidic pH and increased oral bioavailability in monkeys. Further optimization led to the discovery of the clinical candidate 2-[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) (4), the most potent orally active CGRP receptor antagonist described to date.Keywords: MK-3207; calcitonin gene-related peptide; receptor antagonist; pharmacokinetics
01/2010;
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Ian M Bell,
Rodney A Bednar,
Halea A Corcoran,
John F Fay, Steven N Gallicchio,
Victor K Johnston,
James C Hershey,
Cynthia M Miller-Stein,
Eric L Moore,
Scott D Mosser,
Shane A Roller,
Christopher A Salvatore,
Cory R Theberge,
Bradley K Wong,
C Blair Zartman,
Stefanie A Kane,
Theresa M Williams,
Samuel L Graham,
Joseph P Vacca
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ABSTRACT: A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species.
Bioorganic & medicinal chemistry letters 09/2009; 19(16):4740-2. · 2.65 Impact Factor
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Craig A Stump,
Ian M Bell,
Rodney A Bednar,
Joseph G Bruno,
John F Fay, Steven N Gallicchio,
Victor K Johnston,
Eric L Moore,
Scott D Mosser,
Amy G Quigley,
Christopher A Salvatore,
Cory R Theberge,
C Blair Zartman,
Xu-Fang Zhang,
Stefanie A Kane,
Samuel L Graham,
Joseph P Vacca,
Theresa M Williams
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ABSTRACT: Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K(i)=40pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.
Bioorganic & medicinal chemistry letters 11/2008; 19(1):214-7. · 2.65 Impact Factor
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Ian M Bell,
Rodney A Bednar,
John F Fay, Steven N Gallicchio,
Jerome H Hochman,
Daniel R McMasters,
Cynthia Miller-Stein,
Eric L Moore,
Scott D Mosser,
Nicole T Pudvah, [......],
Christopher A Salvatore,
Craig A Stump,
Cory R Theberge,
Bradley K Wong,
C Blair Zartman,
Xu-Fang Zhang,
Stefanie A Kane,
Samuel L Graham,
Joseph P Vacca,
Theresa M Williams
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ABSTRACT: A rapid analogue approach to identification of spirohydantoin-based CGRP antagonists provided novel, low molecular weight leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption. Optimization provided compound 12, a potent CGRP receptor antagonist (K(i)=21nM) with good oral bioavailability in three species.
Bioorganic & Medicinal Chemistry Letters 01/2007; 16(24):6165-9. · 2.55 Impact Factor
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Theresa M Williams,
Craig A Stump,
Diem N Nguyen,
Amy G Quigley,
Ian M Bell, Steven N Gallicchio,
C Blair Zartman,
Bang-Lin Wan,
Kimberly Della Penna,
Priya Kunapuli,
Stefanie A Kane,
Ken S Koblan,
Scott D Mosser,
Ruth Z Rutledge,
Christopher Salvatore,
John F Fay,
Joseph P Vacca,
Samuel L Graham
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ABSTRACT: High-throughput screening of the Merck sample collection identified benzodiazepinone tetralin-spirohydantoin 1 as a CGRP receptor antagonist with micromolar activity. Comparing the structure of 1 with those of earlier peptide-based antagonists such as BIBN 4096 BS, a key hydrogen bond donor-acceptor pharmacophore was hypothesized. Subsequent structure activity studies supported this hypothesis and led to benzodiazepinone piperidinyldihydroquinazolinone 7, CGRP receptor K(i)=44nM and IC(50)=38nM. Compound 7 was orally bioavailabile in rats and is a lead in the development of orally bioavailable CGRP antagonists for the treatment of migraine.
Bioorganic & Medicinal Chemistry Letters 06/2006; 16(10):2595-8. · 2.55 Impact Factor
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Ian M Bell,
Steven M Stirdivant,
Janet Ahern,
J Christopher Culberson,
Paul L Darke,
Christopher J Dinsmore,
Robert A Drakas, Steven N Gallicchio,
Samuel L Graham,
David C Heimbrook, [......],
Annette S Kim,
Maria Kornienko,
Lawrence C Kuo,
Sanjeev K Munshi,
Amy G Quigley,
John C Reid,
B Wesley Trotter,
Lloyd H Waxman,
Theresa M Williams,
C Blair Zartman
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ABSTRACT: The type 1 insulin-like growth factor receptor (IGF-1R) is often overexpressed on tumor cells and is believed to play an important role in anchorage-independent proliferation. Additionally, cell culture studies have indicated that IGF-1R confers increased resistance to apoptosis caused by radiation or chemotherapeutic agents. Thus, inhibitors of the intracellular kinase domain of this receptor may have utility for the clinical treatment of cancer. As part of an effort to develop clinically useful inhibitors of IGF-1R kinase, a novel class of pyrrole-5-carboxaldehyde compounds was investigated. The compounds exhibited selectivity against the closely related insulin receptor kinase intrinsically and in cell-based assays. The inhibitors formed a reversible, covalent adduct at the kinase active site, and treatment of such adducts with sodium borohydride irreversibly inactivated the enzyme. Analysis of a tryptic digest of a covalently modified IGF-1R kinase fragment revealed that the active site Lys1003 had been reductively alkylated with the aldehyde inhibitor. Reductive alkylation of the insulin receptor kinase with one of these inhibitors led to a similarly inactivated enzyme which was examined by X-ray crystallography. The crystal structure confirmed the modification of the active site lysine side chain and revealed details of the key interactions between the inhibitor and enzyme.
Biochemistry 08/2005; 44(27):9430-40. · 3.42 Impact Factor
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Ian M Bell, Steven N Gallicchio,
Marc Abrams,
Lorena S Beese,
Douglas C Beshore,
Hema Bhimnathwala,
Michael J Bogusky,
Carolyn A Buser,
J Christopher Culberson,
Joseph Davide, [......],
Kenneth S Koblan,
Nancy E Kohl,
Robert B Lobell,
Joseph J Lynch,
Ronald Robinson,
A David Rodrigues,
Jeffrey S Taylor,
Eileen S Walsh,
Theresa M Williams,
C Blair Zartman
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ABSTRACT: A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.
Journal of Medicinal Chemistry 07/2002; 45(12):2388-409. · 5.25 Impact Factor
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Ian M. Bell, Steven N. Gallicchio,
Marc Abrams,
Douglas C. Beshore,
Carolyn A. Buser,
J. Christopher Culberson,
Joseph Davide,
Michelle Ellis-Hutchings,
Christine Fernandes,
Jackson B. Gibbs, [......],
Kelem Kassahun,
Kenneth S. Koblan,
Nancy E. Kohl,
Robert B. Lobell,
Joseph J. Lynch, Jr,
Patricia A. Miller,
Charles A. Omer,
A. David Rodrigues,
Eileen S. Walsh,
Theresa M. Williams
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ABSTRACT: The synthesis, structure−activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with excellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of cell potency to intrinsic potency, compared with other known FTIs. It exhibited excellent potency against a range of tumor cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.
Journal of Medicinal Chemistry 07/2001; 44(18). · 5.25 Impact Factor
