Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986)

Article abstract of DOI:10.1021/acs.jmedchem.6b01127

A novel series of second generation DPP1 inhibitors free from aorta binding liabilities found for earlier compound series was discovered. This work culminated in the identification of compound 30 (AZD7986) as a highly potent, reversible, and selective clinical candidate for COPD, with predicted human PK properties suitable for once daily human dosing.

Full text of DOI:10.1021/acs.jmedchem.6b01127

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Discovery of Second
Generation Reversible
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Covalent DPP1 Inhibitors
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Leading to an Oxazepane
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Amidoacetonitrile Based
Clinical Candidate (AZD7986)
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Kevin Doyle, Hans Lönn, Helena Käck,
Amanda Van de Poël, Steve Swallow,
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Philip Gardiner, Stephen Connolly,
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James Root, Cecilia Wikell, Göran Dahl,
Kristina Stenvall, and Petra Johannesson
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J. Med. Chem., Just Accepted Manuscript •
DOI: 10.1021/acs.jmedchem.6b01127
•
Publication Date (Web): 02 Oct 2016
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Discovery of Second Generation Reversible
Covalent DPP1 Inhibitors Leading to an Oxazepane
Amidoacetonitrile Based Clinical Candidate
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(AZD7986)
†
‡
‡
†
§
Kevin Doyle, Hans Lönn, Helena Käck, Amanda Van de Poël, Steve Swallow, Philip
‡
‡
‡
‡
‡
‡
Gardiner, Stephen Connolly, James Root, Cecilia Wikell, Göran Dahl, Kristina Stenvall,
,
‡
Petra Johannesson*
†
Discovery, Charles River, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, U.K.
AstraZeneca Gothenburg, Pepparedsleden 1, Mölndal 431 83, Sweden
‡
§
AstraZeneca Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K.
Abstract
A novel series of second generation DPP1 inhibitors free from aorta binding liabilities found
for earlier compound series was discovered. This work culminated in the identification of
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compound 30 (AZD7986), as a highly potent, reversible and selective clinical candidate for
COPD, with predicted human PK properties suitable for once daily human dosing.
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Introduction
DPP1 (dipeptidyl peptidase 1, or cathepsin C, CatC) is a lysosomal cysteine protease that plays
a key role in the activation of the proinflammatory neutrophil serine proteases (NSPs) neutrophil
1
ꢀ4
elastase (NE), proteinaseꢀ3 (Pr3), and cathepsin G (CatG). Inhibition of DPP1 has therefore
been implicated as a therapeutic treatment of diseases that carry a high neutrophilic burden, such
2, 5, 6
rd
as COPD (chronic obstructive pulmonary disease)
which is projected to be the 3 leading
7
cause of death worldwide by 2030. DPP1 activates NSPs by cleaving the Nꢀterminal dipeptide
during neutrophil maturation in the bone marrow. Inhibition of DPP1 in the bone marrow would
therefore lead to neutrophils without stored active NE, Pr3, or CatG, and has the potential to
reduce the high local release of active NSPs in the lung that cause inflammation and neutrophil
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, 3
driven lung damage (Figure 1).
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Figure 1. Inhibition of DPP1 in the bone marrow delivering neutrophils without stored active
NE, Pr3 or CatG. Part of picture adapted from Blausen.com staff, Wikiversity Journal of
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Medicine 1 (2).
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Human DPP1 is a tetrameric enzyme containing four identical units. Each of the identical
subunits comprises three independent protein chains: the light chain, the heavy chain and the
exclusion domain. The active site which harbours the catalytic cysteine residue (Cys234) is
located at the interface of the three chains. DPP1 has an open S1 site positioned at the entrance
of the active site, while the S2 pocket is large but enclosed within the protein. The exclusion
domain, which is unique for DPP1, blocks access to substrates beyond the S2 site and explains
the exopeptidase activity of DPP1. In addition, the side chain of Asp1 in the exclusion domain
governs substrate recognition by interacting with the
Figure 2).
αꢀamino group of the substrate peptide
(
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Figure 2. Schematic picture of the DPP1 active site, specifically showing the catalytic Cys234
and the Asp1 in the exclusion domain.
The medicinal chemistry of DPP1 has been reviewed and several programs towards
2, 10ꢀ12
developing oral inhibitors have been published.
Most of the reported DPP1 inhibitors are
dipeptidic structures based on preferred substrate motifs where the Cꢀterminus has been modified
to include an electrophilic warhead that reacts through covalent bond formation with the active
site cysteine (Cys234). This covalent interaction can either be reversible or irreversible. The
peptidic and electrophilic nature of DPP1 inhibitors is frequently associated with poor metabolic
2
, 11
stability
as well as presenting a potential safety concern because of high reactivity, potentially
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leading to poor selectivity and consequent offꢀtarget effects. Overcoming such issues is a
serious hurdle and a limited number of DPP1 inhibitors have reached clinical evaluation to date.
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GlaxoSmithKline was the first company to report clinical studies of a DPP1 inhibitor in
healthy humans, completed in 2014 with their irreversible covalent
α
, βꢀunsaturated amide based
(1) (Chart 1) for bronchiectasis. However the development of
this compound was recently reported to have been stopped, due to drug-related adverse events
1
4, 15
DPP1 inhibitor GSK2793660
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and lack of desired effect on biomarkers.
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Chart 1. Examples of known DPP1 inhibitors.
Published reversible DPP1 inhibitors include dipeptide nitriles, and Combio and Merck have
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reported on such amidoacetonitrile based DPP1 inhibitors 2
and 3 respectively (Chart 1).
The nitrile function reacts with the active site cysteine in a Pinner type reaction to form a
1
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reversible thioimidate complex as illustrated in Scheme 1. Thus, with a nonꢀhydrolysable
2
warhead, amidoacetonitriles are competitive DPP1 inhibitors but do not act as substrates.
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Amidoacetonitriles have been successfully used in other advanced development compounds such
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as the cathepsin K inhibitor Odanacatib that reached late clinical development for osteoporosis,
and in the marketed antidiabetic DPP4 inhibitors Saxagliptin and Vildagliptin, thus indicating the
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amidoacetonitrile function as a viable warhead.
Scheme 1. Reaction of the nitrile function with the active site cysteine in a Pinner type reaction
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to form a reversible thioimidate complex.
2
1
We previously reported on our highly potent, selective, and metabolically stable first
generation reversible DPP1 inhibitors that ultimately led to the oral clinical candidate 4, (Scheme
2). Compound 4 showed aortic binding in a rat quantitative wholeꢀbody autoradiography
(QWBA) study leading to its development being terminated prior to human dosing due to safety
2
2
concerns. A mechanistic hypothesis for this finding was established suggesting reactivity with
the aldehyde in allysine side chains that are involved in the crossꢀlinking of elastin, a major
component of aortic tissue. Specifically, we proposed that the chemical reactivity of 4 with the
aldehyde function in allysine occurs via formation of a stable 5ꢀmembered imidazolidinꢀ4ꢀone as
depicted in Scheme 2, and formation of an imidazolidinꢀ4ꢀone through reaction with
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