The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 2

Han, Xiaojun; Civiello, Rita L.; Conway, Charles M.; Cook, Deborah A.; Davis, Carl D.; Degnan, Andrew P.; Jiang, Xiang‐Jun; Macci, Robert; Mathias, Neil; Moench, Paul; Pin, Sokhom S.; Schartman, Richard; Signor, Laura J.; Thalody, George; Tora, George; Whiterock, Valerie J.; Xu, Cen; Macor, John E.; Dubowchik, Gene M.

doi:10.1016/j.bmcl.2013.01.011

Cited by 8 publications

(4 citation statements)

References 19 publications

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“…A further significant boost in binding affinity was realized by the addition of a methyl group at the 7-position of the indazole (34, K i = 0.010 nM, Figure 16), presumably taking better advantage of the tryptophan-lined hydrophobic pocket. 106 The 7-methyl group has been shown to extend into a narrow hydrophobic crevice defined by various hydrophobic RAMP1 residues including Trp74 and Trp84. 107 In addition, the indazole NH formed a hydrogen bond with the Asp71 carboxyl group.…”

Section: ■ Second Generation Oral Compoundsmentioning

confidence: 99%

Blocking the CGRP Pathway for Acute and Preventive Treatment of Migraine: The Evolution of Success

2020

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The pivotal role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology was identified over 30 years ago, but the successful clinical development of targeted therapies has only recently been realized. This Perspective traces the decades long evolution of medicinal chemistry required to advance small molecule CGRP receptor antagonists, also called gepants, including the current clinical agents rimegepant, vazegepant, ubrogepant, and atogepant. Providing clinically effective blockade of CGRP signaling required surmounting multiple challenging hurdles, including defeating a sizable ligand with subnanomolar affinity for its receptor, designing antagonists with an extended confirmation and multiple pharmacophores while retaining solubility and oral bioavailability, and achieving circulating free plasma levels that provided near maximal CGRP receptor coverage. The clinical efficacy of oral and intranasal gepants and the injectable CGRP monoclonal antibodies (mAbs) are described, as are recent synthetic developments that have benefited from new structural biology data. The first oral gepant was recently approved and heralds a new era in the treatment of migraine.

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Section: ■ Second Generation Oral Compoundsmentioning

confidence: 99%

Blocking the CGRP Pathway for Acute and Preventive Treatment of Migraine: The Evolution of Success

2020

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“…Although the resultsd emonstrated that the indazole in 59 offered promise, an interesting observation was that the installation of af luorine substituent at C-8 of the quinazolinone heterocycle led to significantly improved aqueous solubility. [37,38] The synthesis of 59 proceeded via keya mino ester 66, which wasp repared by using the following approach. [37] First, aP d-catalyzedM izoroki-Heck reactionb etween 4-iodo-2,6-dimethylaniline (60)a nd ester 61 conducted at reflux for 3h under N 2 provided intermediate 62,w hich was subjected to a Rh-catalyzed asymmetric hydrogenation in CH 3 OH at room temperature for 16 ht oa fford 64.T he chiral amino ester 64 was treated with isoamyl nitrite in the presence of AcOH/KOAc in toluenef or 16 ht og enerate the indazole moiety of amino ester 65.R emoval of the carboxybenzyl (Cbz) group from 65 under an atmosphere of H 2 gave intermediate 66 (Scheme6).…”

Section: Bms-694153mentioning

confidence: 99%

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Mei

Han

White

et al. 2020

Chemistry A European J

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Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor‐made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man‐made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.

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“…72 Substitution of the indazole ring with a 7-methyl substituent was found to confer an approximately 30-fold increase in CGRP-R affinity. 73 Presumably, this 7-methylindazole moiety is making key interactions with the CGRP receptor that are analogous to those made by the dibromophenol of olcegepant. Importantly, this potency-enhancing modification significantly increased the window between CGRP blockade and CYP inhibition; however, the compounds did not possess the kind of aqueous solubility needed for intranasal dosing.…”

Section: Antagonists From Merckmentioning

confidence: 99%

“…The team undertook an extensive evaluation of alternatives to the central benzothiophenyl moiety and identified indazol-5-yl as an attractive replacement, affording compound 18 : a subnanomolar CGRP receptor antagonist ( K i = 0.23 nM) with attenuated CYP inhibition (CYP3A4 IC 50 = 4.0 μM) . Substitution of the indazole ring with a 7-methyl substituent was found to confer an approximately 30-fold increase in CGRP-R affinity . Presumably, this 7-methylindazole moiety is making key interactions with the CGRP receptor that are analogous to those made by the dibromophenol of olcegepant.…”

Section: Indazole-based Cgrp Receptor Antagonists From Bmsmentioning

confidence: 99%

Calcitonin Gene-Related Peptide Receptor Antagonists: New Therapeutic Agents for Migraine

Bell

2014

J. Med. Chem.

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Calcitonin gene-related peptide (CGRP) is a potent neuromodulator and vasodilator. It has been implicated in the pathogenesis of migraine by a number of lines of evidence, although its precise role has yet to be fully defined. Compelling evidence for the importance of CGRP in migraine has been provided by clinical trials with multiple small molecule CGRP receptor antagonists. These clinical studies have shown that blockade of the CGRP receptor can produce antimigraine efficacy comparable to that of the gold standard triptan class of drugs with an incidence of adverse events that appears to be relatively low. The present review describes the discovery and development of these new antimigraine agents and highlights the challenges of identifying orally acting drugs that target a family B G-protein-coupled receptor.

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The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 2

Cited by 8 publications

References 19 publications

Blocking the CGRP Pathway for Acute and Preventive Treatment of Migraine: The Evolution of Success

Blocking the CGRP Pathway for Acute and Preventive Treatment of Migraine: The Evolution of Success

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Calcitonin Gene-Related Peptide Receptor Antagonists: New Therapeutic Agents for Migraine

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