Oxazepane DPP1 Inhibitors With Reduced Elastin Tissue Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current inhibitors for dipeptidyl peptidase 1 (DPP1) do not effectively address the role of this enzyme in activating proteases associated with allergic and inflammatory diseases, particularly in conditions like asthma and chronic obstructive pulmonary disease (COPD), and may have undesirable side effects such as binding to elastin-rich tissues.
Innovation Solution
Development of (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compounds that act as potent DPP1 inhibitors, reducing the activity of DPP1, neutrophil elastase, cathepsin G, and proteinase-3, thereby mitigating the inflammatory response in respiratory diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing DPP1 inhibitors are used, then DPP1 activity is reduced, but they bind to elastin-rich tissues causing undesirable side effects
Solution Approach 1:
The patent applies local quality by introducing a specific chiral center with (2S) configuration at the oxazepane ring position 2, which creates selective interactions with DPP1's active site while avoiding binding to elastin-rich tissues. This stereochemical feature provides tissue-selective activity, allowing the inhibitor to target DPP1 in respiratory tissues without causing harmful binding to elastin-containing structures.
Solution Approach 2:
The patent utilizes asymmetry through the (2S) chiral configuration of the oxazepane ring, creating an asymmetric molecular structure that fits precisely into DPP1's asymmetric active site. This chiral asymmetry enables selective binding to DPP1 while preventing interaction with elastin-rich tissues, thereby resolving the contradiction between effective inhibition and harmful tissue binding.
2Reliability
If DPP1 inhibitors are used to reduce protease activity, then inflammation is reduced, but current inhibitors do not effectively address protease activation in allergic diseases
Solution Approach 1:
The patent applies parameter changes by optimizing the molecular parameters of the inhibitor, specifically the (2S) chiral configuration and the oxazepane ring structure, to enhance affinity and specificity for DPP1. This structural optimization allows the inhibitor to effectively block protease activation in the context of allergic and inflammatory diseases, improving adaptability to various disease states.
Data Source
AI summary
The present disclosure relates to certain (2S)—N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compounds (including pharmaceutically acceptable salts thereof),that inhibit dipeptidyl peptidase 1 (DPP1) activity, to their utility in treating and/or preventing clinical conditions including respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), to their use in therapy, to pharmaceutical compositions containing them and to processes for preparing such compounds.