Identification of dissociated non-steroidal glucocorticoid receptor agonists

Kuzmich, Daniel; Kirrane, Tom; Proudfoot, John; Bekkali, Younes; Zindell, Renée; Beck, Laura; Nelson, Richard M.; Shih, Cheng-Kon; Kukulka, Alison; Paw, Zofia; Reilly, Patty; DeLeon, Rodney P.; Cardozo, Mario; Nabozny, Gerald H.; Thomson, D. S.

doi:10.1016/j.bmcl.2007.07.031

Cited by 34 publications

(8 citation statements)

References 30 publications

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“…Evidence of the clear interest in the field of non-steroidal dissociated GR ligands is provided by the considerable number of compounds reported (reviewed in [60]) that are able to bind GR with a more favorable profile as compared to standard classic GCs. These include Boehringer Ingelheim's BI 115 and Compound 36 [61], GSK's tetrahydronaphthaline-methylbenzoxazinones [62] and arylpyrazoles [63] or a 6,5-bicyclic core fused to a pyrazole ring (Merck) [64], Compound 15 (UCSF), Compound 25 (Merck), or the recently reported Compound 2 (Pfizer) [65]. Data on side effect parameters are still lacking for many of these compounds.…”

Section: Non-steroidal Gr Modulatorsmentioning

confidence: 98%

“…In recent years it has become clear that hGR␣ mRNA can be translated from at least eight alternative initiation sites into multiple GR␣ isoforms, termed GR␣-A to D (A, B, C1, C2, C3, D1, D2 and D3), and which display different expression patterns depending on the tissue type (reviewed in [69,61,62]). Therefore, not only the different ligands but also the pre-existence in a particular tissue type of different receptor isoforms will co-determine the biological response.…”

Section: Impact Of Gr˛variants?mentioning

confidence: 99%

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Selective Glucocorticoid Receptor modulators

Bosscher

2010

The Journal of Steroid Biochemistry and Molecular Biology

113

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Section: Non-steroidal Gr Modulatorsmentioning

confidence: 98%

Section: Impact Of Gr˛variants?mentioning

confidence: 99%

Selective Glucocorticoid Receptor modulators

Bosscher

2010

The Journal of Steroid Biochemistry and Molecular Biology

113

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“…They identify a development candidate, with BI-54903 commencing clinical studies in 2011 [46]. BI-54903 appears to have been derived from the optimization of a series of pyrrolo [2,3-c]pyridines such as BI-115 [47]. However, Boehringer Ingelheim terminated three Phase II trial in asthma in USA (NCT01397162, NCT01397201, NCT01396278) and no information on Phase I studies in asthma has been reported [48].…”

Section: Bi-54903mentioning

confidence: 99%

Novel glucocorticoid receptor agonists in the treatment of asthma

Cazzola

Coppola

Rogliani

et al. 2015

Expert Opinion on Investigational Drugs

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Several agents have been synthesized, but few have been tested in experimental models of asthma. Furthermore, only three (BI-54903, GW870086X and AZD5423) have entered clinical development, although the development of at least one of them (BI-54903) was discontinued. The reason for the limited success so far obtained is that the model of transactivation versus transrepression is a too simplistic representation of GR activity. It is difficult to uncouple the therapeutic and harmful effects mediated by GR, but some useful information that might change the current perspective is appearing in the literature. The generation of gene expression 'fingerprints' produced by different GR agonists in target and off-target human tissues could be useful in identifying drug candidates with an improved therapeutic ratio.

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“…These complications often hamper high dose and chronic administration. The search for non‐steroidal drugs that would have the desired anti‐inflammatory actions of GC but with significantly lower or no side effects remains an ongoing quest . Herein, we report the synthesis of two potent GR agonists labeled with carbon‐14 and with stable isotopes to aid in drug metabolism, pharmacokinetics, and bioanalytical and other studies (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of two potent glucocorticoid receptor agonists labeled with carbon‐14 and stable isotopes

Latli

Reeves

Tan

et al. 2015

Labelled Comp Radiopharmac

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Two potent glucocorticoid receptor agonists were prepared labeled with carbon-14 and with stable isotopes to perform drug metabolism, pharmacokinetics, and bioanalytical studies. Carbon-14 labeled (1) was obtained from an enantiopure alkyne (5) via a Sonogashira coupling to a previously reported 5-amino-4-iodo-[2-(14)C]pyrimidine [(14)C]-(6), followed by a base-mediated cyclization (1) in 72% overall radiochemical yield. Carbon-14 labeled (2) was prepared in five steps employing a key benzoic acid intermediate [(14)C]-(13), which was synthesized in one pot from enolization of trifluoromethylketone (12), followed by bromine-magnesium exchange and then electrophile trapping reaction with [(14)C]-carbon dioxide. A chiral auxiliary (S)-1-(4-methoxyphenyl)ethylamine was then coupled to this acid to give [(14)C]-(15). Propargylation and separation of diastereoisomers by crystallizations gave the desired diastereomer [(14)C]-(17) in 34% yield. Sonogashira coupling to iodopyridine (10) followed by cyclization to the azaindole [(14)C]-(18) and finally removal of the chiral auxiliary gave [(14)C]-(2) in 7% overall yield. For stable isotope syntheses, [(13)C6]-(1) was obtained in three steps using [(13)C4]-(6) and trimethylsilylacetylene-[(13)C2] in 26% yield, while [(2)H5]-(2) was obtained by first preparing the iodopyridine [(2)H5]-(10) in five steps. Then, Sonogashira coupling to chiral alkyne (24) and cyclization gave [(2)H5]-(2) in 42% overall yield.

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Identification of dissociated non-steroidal glucocorticoid receptor agonists

Cited by 34 publications

References 30 publications

Selective Glucocorticoid Receptor modulators

Selective Glucocorticoid Receptor modulators

Novel glucocorticoid receptor agonists in the treatment of asthma

Synthesis of two potent glucocorticoid receptor agonists labeled with carbon‐14 and stable isotopes

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