Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986).
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.
Discovery, Charles River , Chesterford Research Park, Saffron Walden, Essex CB10 1XL, U.K.
Kevin
K
Doyle
AstraZeneca Gothenburg , Pepparedsleden 1, Mölndal 431 83, Sweden.
Hans
H
Lönn
AstraZeneca Gothenburg , Pepparedsleden 1, Mölndal 431 83, Sweden.
Helena
H
Käck
Discovery, Charles River , Chesterford Research Park, Saffron Walden, Essex CB10 1XL, U.K.
Amanda
A
Van de Poël
AstraZeneca Alderley Park , Macclesfield, Cheshire SK10 4TG, U.K.
Steve
S
Swallow
AstraZeneca Gothenburg , Pepparedsleden 1, Mölndal 431 83, Sweden.
Philip
P
Gardiner
AstraZeneca Gothenburg , Pepparedsleden 1, Mölndal 431 83, Sweden.
Stephen
S
Connolly
AstraZeneca Gothenburg , Pepparedsleden 1, Mölndal 431 83, Sweden.
James
J
Root
AstraZeneca Gothenburg , Pepparedsleden 1, Mölndal 431 83, Sweden.
Cecilia
C
Wikell
AstraZeneca Gothenburg , Pepparedsleden 1, Mölndal 431 83, Sweden.
Göran
G
Dahl
AstraZeneca Gothenburg , Pepparedsleden 1, Mölndal 431 83, Sweden.
Kristina
K
Stenvall
AstraZeneca Gothenburg , Pepparedsleden 1, Mölndal 431 83, Sweden.
Petra
P
Johannesson
D000284:Administration, Oral; D000818:Animals; D001583:Benzoxazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D020789:Cathepsin C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010077:Oxazepines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D020298:U937 Cells
D001583:Benzoxazoles; D020789:Cathepsin C; D010077:Oxazepines; D011480:Protease Inhibitors; C000619932:brensocatib; C533918:CTSC protein, human