Development of Orally Bioavailable and CNS Penetrant Biphenylaminocyclopropane Carboxamide Bradykinin B<sub>1</sub> Receptor Antagonists

Kuduk, Scott D.; Marco, Christina N. Di; Chang, Ronald K.; Wood, Michael R.; Schirripa, Kathy M.; Kim, June J.; Wai, Jenny M.; DiPardo, Robert M.; Murphy, Kathy; Ransom, Richard W.; Harrell, C. Meacham; Reiss, Duane R.; Holahan, Marie A.; Cook, Jacquelynn J.; Hess, J. Fred; Sain, Nova; Urban, Mark O.; Tang, Cuyue; Prueksaritanont, Thomayant; Pettibone, Douglas J.; Bock, Mark G.

doi:10.1021/jm061094b

Cited by 51 publications

(26 citation statements)

References 25 publications

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“…91 Passive membrane permeability and P-gp efflux ratios were improved by an analogous tactical approach applied to a series of CNS-penetrant bradykinin B1 antagonists that were explored as potential agents for the relief of pain (Table 15). 93 The introduction of fluorine atoms into the acetamide moiety of 188 resulted in compounds 189−191 which demonstrated improved profiles. This was attributed to a reduction in the strength of the terminal amide carbonyl to function as an H-bond acceptor, although an intramolecular interaction between the fluorine atoms and the N−H may also contribute.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Applications of Fluorine in Medicinal Chemistry

et al. 2015

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The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, (18)F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Applications of Fluorine in Medicinal Chemistry

et al. 2015

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“…Moreover, compound 118-related structures were found to be substrates of P-gp, thereby compromising their CNS penetration. 154 Therefore, the same research group 155 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 42 type of receptor may be useful in the treatment of daytime sleepiness, narcolepsy and ADHD. 159 Letavic et al, 160 began medicinal chemistry work to synthesize H 3 receptor antagonists with piperazinecarbonyl benzylamine as a lead scaffold.…”

Section: Bradykinin B1 Receptor Antagonist 120mentioning

confidence: 99%

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

2016

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Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,

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“…1) was used in a clinical trial for the prevention of brain edema after head injury (an inconclusive trial). 12 The clinical development of the brain penetrant B 1 R antagonist MK-0686 13 as an analgesic was interrupted after at least 2 trials for inflammatory pain, apparently because of lack of efficacy. 11 The anti-inflammatory effect of kinin receptor antagonists, well established in numerous preclinical studies, has not been evaluated in humans, but is of considerable potential interest.…”

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confidence: 99%

Bradykinin receptors: Agonists, antagonists, expression, signaling, and adaptation to sustained stimulation

Marceau

Bachelard

Bouthillier

et al. 2020

International Immunopharmacology

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The Journal of Angioedemasit amet INTRODUCTION The pharmacology of bradykinin (BK)-related peptides, the kinins, has come a long way in recent decades, with the pharmacologic and then the molecular definition of 2 G protein-coupled receptors (GPCRs) that mediate their cellular actions, the B 1 and B 2 receptors (B 1 R, B 2 R). 1 Additional modern research tools include mouse strains in which one or both of the genes coding for kinin receptors have been deleted ("gene knockout" models). 2 The formation of kinins and their degradation by interesting peptidases, such as angiotensin-converting enzyme, will not be covered in the present text. The arduous nature of the analytic biochemistry of BK-related peptides is outlined elsewhere. 3 We rather propose an excursion into the pharmacology of kinins, the first author having been a spectator and an actor in the field for the past 35 years. There will be a strong autobiographic bias in the selection of the illustration material. We hope this partiality will be forgiven in light of the generous invitation he has received to summarize the field during an oral presentation at the 8th C1-Inhibitor Deficiency Workshop. BRADYKININ RECEPTOR LIGANDS: AGONISTS AND ANTAGONISTS The receptors for bradykinin were initially defined in the late 1970s and 1980s using pharmacologic criteria. The B 1 R was historically the first defined using both a typical potency order of agonists and a class of specific antagonists. This somewhat atypical receptor subtype is optimally responsive to fragments of the native kinins (BK and Lys-BK) in which the Arg 9 residue has been removed (des-Arg 9-BK, Lys-des-Arg 9-BK, respectively; Fig. 1). 4 The early peptide antagonists were simply des-Arg 9 sequences in which Phe 8 was replaced with a residue possessing an aliphatic side chain, such as Leu. In retrospect, it is now clear that the native kinins produced by the kallikreins, either BK or Lys-BK (kallidin), are selective agonists of the physiologically prominent B 2 R subtype that has been consolidated with specific peptide antagonists in the 1980s by Professor John M. Stewart and colleagues. The B 2 R antagonists typically possess a constrained peptide backbone due to the inclusion of bulky nonnatural amino acids that also confer resistance ABSTRACT Bradykinin-related peptides, the kinins, are blood-derived peptides that stimulate 2 G protein-coupled receptors, the B 1 and B 2 receptors (B 1 R, B 2 R). The pharmacologic and molecular identities of these 2 receptor subtypes will be succinctly reviewed, with emphasis on drug development, receptor expression, signaling, and adaptation to persistent stimulation. Peptide and nonpeptide antagonists and fluorescent ligands have been produced for each receptor. The B 2 R is widely and constitutively expressed in mammalian tissues, whereas the B 1 R is mostly inducible under the effect of cytokines during infection and immunopathology. Both receptor subtypes mediate the vascular aspects of inflammation (vasodilation, edema formation). On this basis, icatibant...

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Development of Orally Bioavailable and CNS Penetrant Biphenylaminocyclopropane Carboxamide Bradykinin B₁ Receptor Antagonists

Cited by 51 publications

References 25 publications

Applications of Fluorine in Medicinal Chemistry

Applications of Fluorine in Medicinal Chemistry

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

Bradykinin receptors: Agonists, antagonists, expression, signaling, and adaptation to sustained stimulation

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Development of Orally Bioavailable and CNS Penetrant Biphenylaminocyclopropane Carboxamide Bradykinin B1 Receptor Antagonists

Cited by 51 publications

References 25 publications

Applications of Fluorine in Medicinal Chemistry

Applications of Fluorine in Medicinal Chemistry

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

Bradykinin receptors: Agonists, antagonists, expression, signaling, and adaptation to sustained stimulation

Contact Info

Product

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Development of Orally Bioavailable and CNS Penetrant Biphenylaminocyclopropane Carboxamide Bradykinin B₁ Receptor Antagonists