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1.
ACS Med Chem Lett ; 4(9): 863-8, 2013 Sep 12.
Article in English | MEDLINE | ID: mdl-24900761

ABSTRACT

Rational modification of the potent calcitonin gene-related peptide (CGRP) receptor antagonist MK-3207 led to a series of analogues with enhanced CNS penetrance and a convenient chemical handle for introduction of a radiolabel. A number of (11)C-tracers were synthesized and evaluated in vivo, leading to the identification of [(11)C]8 ([(11)C]MK-4232), the first positron emission tomography tracer for the CGRP receptor.

2.
Bioorg Med Chem Lett ; 22(12): 3941-5, 2012 Jun 15.
Article in English | MEDLINE | ID: mdl-22607672

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.


Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Migraine Disorders/drug therapy , Pyridines/chemical synthesis , Pyridines/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Administration, Oral , Analgesics/blood , Animals , Biological Availability , Disease Models, Animal , Dogs , Humans , Macaca mulatta , Mice , Pyridines/blood , Rats , Receptors, Calcitonin Gene-Related Peptide/metabolism , Species Specificity , Spiro Compounds/blood
3.
Bioorg Med Chem Lett ; 21(22): 6705-8, 2011 Nov 15.
Article in English | MEDLINE | ID: mdl-21982500

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.


Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Receptor Activity-Modifying Proteins/metabolism , Receptors, Calcitonin Gene-Related Peptide/metabolism , Animals , Cell Line , Dogs , HIV/enzymology , HIV Integrase Inhibitors/pharmacokinetics , Humans , Protein Binding , Pyridines/pharmacokinetics , Rats
4.
Bioorg Med Chem Lett ; 20(8): 2572-6, 2010 Apr 15.
Article in English | MEDLINE | ID: mdl-20299218

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.


Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Quinolines/pharmacology , Animals , Biological Availability , Dogs , Drug Evaluation, Preclinical , Macaca mulatta , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats
5.
ACS Med Chem Lett ; 1(1): 24-9, 2010 Apr 08.
Article in English | MEDLINE | ID: mdl-24900170

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.

6.
Bioorg Med Chem Lett ; 18(23): 6122-5, 2008 Dec 01.
Article in English | MEDLINE | ID: mdl-18947992

ABSTRACT

The previously disclosed spirohydantoin-based CGRP receptor antagonists were optimized for potency through modification of the benzimidazolone substituents. Compounds were identified which had minimal shift in the cAMP functional assay containing 50% human serum. Blockade of CGRP-mediated vasodilation was observed with these compounds in a rhesus pharmacodynamic assay and the in vivo potency correlated with the in vitro activity in the serum-shifted functional assay.


Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Indans/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Animals , Benzimidazoles/blood , Benzimidazoles/chemistry , Combinatorial Chemistry Techniques , Humans , Macaca mulatta , Molecular Structure , Spiro Compounds/chemistry , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 16(24): 6165-9, 2006 Dec 15.
Article in English | MEDLINE | ID: mdl-17027263

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.


Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Hydantoins/pharmacology , Hydantoins/pharmacokinetics , Spiro Compounds/pharmacology , Spiro Compounds/pharmacokinetics , Administration, Oral , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Biological Availability , Cell Line , Humans , Hydantoins/chemistry , Kidney , Models, Molecular , Molecular Structure , Spiro Compounds/chemistry , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 16(10): 2595-8, 2006 May 15.
Article in English | MEDLINE | ID: mdl-16527483

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.


Subject(s)
Benzodiazepinones/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Animals , Benzodiazepinones/pharmacokinetics , Biological Availability , Cell Line , Humans , Hydrogen Bonding , Rats , Structure-Activity Relationship
9.
Biochemistry ; 45(6): 1881-7, 2006 Feb 14.
Article in English | MEDLINE | ID: mdl-16460034

ABSTRACT

The calcitonin-like receptor (CLR) and the calcitonin receptor (CTR) interact with receptor activity-modifying protein 1 (RAMP1) at the cell surface to form heterodimeric receptor complexes. CLR and CTR are members of the class II (family B) G-protein-coupled receptors (GPCR) and bind calcitonin gene-related peptide (CGRP) with similar affinities when coexpressed with RAMP1. The observation that various nonpeptide CGRP receptor antagonists display a higher affinity for the CLR/RAMP1 complex than for CTR/RAMP1 provided an opportunity to investigate the molecular determinants of the differential receptor affinities of these antagonists. A chimeric receptor approach was utilized to identify key domains within CLR responsible for conferring high-affinity antagonist binding. Initial chimera experiments implicated distinct regions within CLR as responsible for the affinities of structurally diverse CGRP receptor antagonists. Dissection of these key regions implicated amino acids 37-63 located in the amino terminus of CLR as responsible for the high-affinity interaction of one structural class, while transmembrane domain (TM) 7 was responsible for the interaction of a second class of antagonist. A unique binding interaction in the amino terminus of CLR is consistent with the observation that these compounds also interact with the extracellular region of RAMP1 and could suggest the formation of a binding pocket between the two proteins. Conversely, a compound which interacted with TM7 did not display a similar RAMP1 dependence, suggesting an allosteric mechanism of antagonism. Collectively, these data provide insight into two alternative mechanisms of antagonism for this unique heterodimeric receptor complex.


Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Receptors, Calcitonin/metabolism , Base Sequence , Binding, Competitive , Calcitonin Receptor-Like Protein , Cell Membrane/metabolism , Cells, Cultured , Humans , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Ligands , Membrane Proteins/chemistry , Membrane Proteins/genetics , Membrane Proteins/metabolism , Receptor Activity-Modifying Protein 1 , Receptor Activity-Modifying Proteins , Receptors, Calcitonin Gene-Related Peptide/metabolism , Receptors, G-Protein-Coupled/metabolism , Signal Transduction
10.
Biochemistry ; 44(27): 9430-40, 2005 Jul 12.
Article in English | MEDLINE | ID: mdl-15996097

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.


Subject(s)
Aldehydes/chemistry , Protein Kinase Inhibitors/chemistry , Pyrroles/chemistry , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, Insulin/antagonists & inhibitors , Receptor, Insulin/chemistry , Aldehydes/metabolism , Amino Acid Sequence , Binding Sites , Borohydrides/chemistry , Cell Line , Crystallography, X-Ray , Enzyme Activation , Humans , Molecular Sequence Data , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Phosphorylation , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Pyrroles/metabolism , Receptor, Insulin/metabolism , Schiff Bases/chemistry , Structure-Activity Relationship
11.
Rapid Commun Mass Spectrom ; 19(5): 667-73, 2005.
Article in English | MEDLINE | ID: mdl-15700234

ABSTRACT

Electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) are the two most common mass spectrometric ionization methods used in the pharmaceutical industry. However, APCI analysis can sometimes lead to ambiguity in compound characterization and quantitation due to gas-phase reactions occurring between acetonitrile and water in the plasma, and between these plasma-generated compounds and the analyte. During the analysis of various sultams and sulfonamides we observed signals corresponding to m/z [M+44](+) and [M+60](+). Various solvent conditions and collisionally activated dissociation MS(n) experiments revealed that under the high-energy plasma conditions of APCI, the acetonitrile/water solvent mixture reacts undergoing acid-catalyzed hydrolysis producing acetamide, 59 Da. Further, the highly reactive 43 Da species ethanimine is also produced. These two compounds, normally not observed in APCI analysis, are stabilized by the sulfonamide and appear as adduct species in the mass spectra. The sulfone oxygens and the lone pair of electrons on the amide nitrogen play a role in stabilizing this adduct.


Subject(s)
Acetonitriles/analysis , Acetonitriles/chemistry , Spectrometry, Mass, Electrospray Ionization/methods , Sulfonamides/analysis , Sulfonamides/chemistry , Water/analysis , Water/chemistry , Atmospheric Pressure , Gases/analysis , Gases/chemistry , Phase Transition
13.
J Med Chem ; 45(12): 2388-409, 2002 Jun 06.
Article in English | MEDLINE | ID: mdl-12036349

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.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Aryl Hydrocarbon Hydroxylases , Cation Transport Proteins , DNA-Binding Proteins , Enzyme Inhibitors/chemical synthesis , Naphthalenes/chemical synthesis , Potassium Channels, Voltage-Gated , Pyrrolidines/chemical synthesis , Trans-Activators , Animals , Cell Line , Chromatography, Liquid , Crystallography, X-Ray , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Dogs , ERG1 Potassium Channel , Electrocardiography , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Ether-A-Go-Go Potassium Channels , Farnesyltranstransferase , Humans , In Vitro Techniques , Magnetic Resonance Spectroscopy , Mass Spectrometry , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Models, Molecular , Molecular Structure , Naphthalenes/chemistry , Naphthalenes/pharmacokinetics , Oxidoreductases, N-Demethylating/antagonists & inhibitors , Potassium Channels/metabolism , Protein Binding , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Stereoisomerism , Structure-Activity Relationship , Transcriptional Regulator ERG
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