Tetrahedron Letters
Keeping it small, polar, and non-flat: diversely functionalized
building blocks containing the privileged 5,6,7,8-tetrahydro
[1,2,4]triazolo[4,3-a]- and [1,5-a]pyridine cores
Alexander Mishchuk a, Natalia Shtil b, Mykola Poberezhnyk c, Konstiantyn Nazarenko a,b
,
Timur Savchenko a, Andrey Tolmachev a, Mikhail Krasavin d,
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a Enamine Ltd, 78 Chervonotkatska, Kyiv 02094, Ukraine
b Institute of Organic Chemistry of the NAS of Ukraine, 5, Murmanska Str., Kyiv 02660, Ukraine
c Taras Shevchenko National University of Kyiv, 64/13, Volodymyrska Street, Kyiv 01601, Ukraine
d Institute of Chemistry, St. Petersburg State University, Peterhof 198504, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Six sets of functionalized building blocks based on 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine as well
as 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine cores have been prepared. These compounds are non-
flat, bicyclic heterocycles that are likely to find utility as privileged motifs for lead-like compound design.
One set of building blocks, (5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-6-ylmethyl)amines, proved
useful as a scaffold for developing compounds that stimulate glucagon-like peptide-1 (GLP-1) secretion
and are novel anti-diabetes drug leads.
Received 27 November 2015
Revised 22 January 2016
Accepted 26 January 2016
Available online xxxx
Keywords:
Ó 2016 Elsevier Ltd. All rights reserved.
Lead-oriented synthesis
Non-flat heterocycles
Hydrogenation
Dimroth rearrangement
Anti-diabetes drugs
The modern design of small molecules for bioactivity screening
appears to be significantly be influenced by two major concepts,
namely, those of lead-likeness and ‘non-flatness’. Lead-like com-
pounds1 conform to more stringent criteria of lipophilicity (logP)
and molecular weight (MW) compared to the Lipinski ‘rule-of-five’
chemical space.2 Lead-likeness offers ample room for medicinal
chemistry optimization, which normally results in increasing a
molecule’s size and lipophilicity. Noticeably, compounds in current
screening collections (proprietary or commercially available) fill
the higher-end space of the Lipinski boundaries while the lead-like
space is scarcely populated.3 In response to this obvious void, the
term ‘lead-oriented synthesis’ (LOS) was coined by a GlaxoSmithK-
line team4 to signify the synthetic organic chemistry methodolo-
gies capable of primarily delivering lead-like compounds. While
being a technically more challenging concept to implement,5 LOS
has become a necessary challenge for organic chemists to face, as
the current productivity crisis in pharmaceutical industry6 is fre-
quently linked to the lack of quality drug leads emerging from
screening.7 The concept of ‘non-flatness’, that is, increasing a mole-
cule’s three-dimensional character by reducing the number of flat
aromatic rings (or increasing the fraction of sp3-hybridized heavy
atoms, Fsp3) has also gained a particular importance after it was
noted that, on a statistical level, compounds become more satu-
rated as they progress through the drug development cycle.8
Besides this pure statistical significance, more ‘shapeliness’ for a
compound means being more complimentary to its protein target,
more selective against off-targets, less toxic, and, ultimately, more
successful in the drug development cycle.
The 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine core (1) as
well as its bioisosteric 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyri-
dine counterpart (2) clearly incorporate the aforementioned fea-
tures, considering their low molecular weight (123), high
hydrophilicity (cLogP ꢀÀ0.179), and the saturation of the pyridine
ring, while preserving the essential 1,2,4-triazole moiety (Fig. 1).
While preparation of these cores by partial reduction of their fully
aromatic congeners was well established several decades ago,10,11
only recently have we seen their advent (of 1 in particular) in var-
ious drug leads. Notable examples include modulators of c-secre-
tase (an important target in Alzheimer’s disease) from Janssen
Pharmaceutica (3)12 and Takeda (4),13 multi-target anti-inflamma-
tory compound 514 from Pharmacia & Upjohn, as well as inhibitors
of dipeptidyl peptidase IV (DPPIV) from Merck (6)15 and The
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Corresponding author. Tel.: +7 931 3617872; fax: +7 812 428 6939.
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