Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies

Devasthale, Pratik; Wang, Wei; Mignone, James; Renduchintala, Kishore; Radhakrishnan, Sridhar; Dhanapal, Jayanthi; Selvaraj, Jagannath; Kuppusamy, Rajesh; Pelleymounter, Mary Ann; Longhi, Daniel Angelo; Flynn, Neil; Azzara, Anthony V.; Rohrbach, Kenneth W.; Devenny, James J.; Rooney, Suzanne; Thomas, Michael A.; Glick, Susan; Godonis, Helen E.; Harvey, Susan J.; Cullen, Mary Jane; Zhang, Hongwei; Caporuscio, Christian; Stetsko, Paul; Grubb, Mary F.; Huang, Christine; Zhang, Lisa; Freeden, Chris; Murphy, Brian J.; Robl, Jeffrey A.; Washburn, William N.

doi:10.1016/j.bmcl.2015.09.018

Cited by 11 publications

(4 citation statements)

References 10 publications

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“…48,49 On the contrary, the tetraline ring does not have a hydrogen-bonding interaction with any nearby amino acid residue in compound 1. 42 Inspired by this model and a recent report of nonbasic MCHR1 antagonists by Washburn et al, 50,51 we hypothesized that the aliphatic amine could be removed without loss of binding affinity if the bicyclic motif actively interacts with the receptor via hydrogen bonding, thus leading to amine-free MCHR1 antagonists without hERG liability (Figure 3). Our molecular modeling studies suggested that Asp123 and Tyr272 were possible interaction counterparts of the bicyclic motif in our model.…”

Section: ■ Introductionmentioning

confidence: 94%

Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives

et al. 2016

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Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of pK(a) < 8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chemical space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo[1,2-a]pyridine ring (represented in compounds 6a and 6b), and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)oxy]-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one 10a. It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet-induced obese rats.

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Section: ■ Introductionmentioning

confidence: 94%

Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives

et al. 2016

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“…Anthracene‐containing triphenyl amine donor moiety 1 , benzotriazole‐containing acceptor moiety 3 , benzothiadiazole‐containing acceptor moiety 4 , and meso ‐substituted porphyrin precursor 5 were prepared as previously reported [4c, 18] . The key intermediate pyrrole 10 was synthesized via Suzuki coupling using bromopyrrole 9 and boronic acid 8 which were prepared as reported procedures [18a, 19] . The reaction of pyrrole 10 with dimethoxymethane afforded dipyrrylmethane 11 , which was then decarboxylated under alkaline conditions to give 12 .…”

Section: Resultsmentioning

confidence: 99%

Double Fence Porphyrins that are Compatible with Cobalt(II/III) Electrolyte for High‐Efficiency Dye‐Sensitized Solar Cells

Chen

Nguyễn

et al. 2021

Angewandte Chemie

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A series of new double fence porphyrin dyes bJS1–bJS3, with eight long alkoxyl chains attached to four β‐phenyl groups, have been designed and synthesized. The single fence meso‐substituted counterparts mJS1–mJS3 were also prepared as reference dyes. Dyes bJS1–bJS3 and mJS1–mJS3 exhibit power conversion efficiencies of 8.03–10.69 % and 2.33–6.69 %, respectively. Based on photovoltaic studies, the remarkable cell performance of double fence porphyrin sensitizers can be attributed to reduced dye aggregation and a decreased charge‐recombination rate. Notably, porphyrins bJS2 and bJS3 exhibit better efficiency than the benchmark YD2‐o‐C8 (9.83 % in this work), demonstrating that the double fence structure is a promising design strategy for efficient porphyrin sensitizers in high‐performance DSSCs.

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“…Devasthale et al [13] have designed a series of pyrrolotriazinones that were assayed for their antagonistic activity, and the reduction in weight gain in a rat model after 4 days of once-daily oral treatment. Among the tested compounds that exhibited the best brain concentrations, compound 3 (Figure 4) showed the best results, with an MCHR1 inhibition constant (Ki) of 2.3 nM (human) and 1.8 nM (rat) and an impressive 6.9% weight reduction in rat model relative to vehicle after 4 days.…”

Section: Mchr1 Antagonistsmentioning

confidence: 99%

Pyrrolotriazinone as an Underexplored Scaffold in Drug Discovery

Cintrat

2021

Pharmaceuticals

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Heterocyclic amino derivatives have been extensively synthesized and validated as potent bioactive compounds, and nowadays, numerous marketed drugs share these scaffolds, from very simple structures (monoamino, monocyclic compounds) to much more complex molecules (polycyclic derivatives with two or more nitrogen atoms within the (fused) rings). In a constant quest for new chemical entities in drug discovery, a few novel heterocycles have emerged in recent years as promising building blocks for the obtainment of bioactive modulators. In this context, pyrrolotriazinones have attracted attention, and some show promising biological activities. Here, we offer an extensive review of pyrrolo[2,1-f][1,2,4]triazin-4(1H)-one and pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one, describing their biological properties en route to drug discovery.

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Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies

Cited by 11 publications

References 10 publications

Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives

Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives

Double Fence Porphyrins that are Compatible with Cobalt(II/III) Electrolyte for High‐Efficiency Dye‐Sensitized Solar Cells

Pyrrolotriazinone as an Underexplored Scaffold in Drug Discovery

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