title: Design and synthesis of inhaled p38 inhibitors for the treatment of chronic obstructive pulmonary disease.
abstract: This paper describes the identification and optimization of a novel series of DFG-out binding p38 inhibitors as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure based drug design and "inhalation by design" principles have been applied to the optimization of the lead series exemplied by compound 1a. Analogues have been designed to be potent and selective for p38, with an emphasis on slow enzyme dissociation kinetics to deliver prolonged lung p38 inhibition. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimize systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance and glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimize drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity, and solubility were considered to ensure compatibility with a dry powder inhaler. 1ab (PF-03715455) was subsequently identified as a clinical candidate from this series with efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of COPD.
authors: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , Sandwich Laboratories, Ramsgate Road, Sandwich, Kent, CT13 9NJ, U.K. david.millan@gmail.com
authors: David S
authors: DS
authors: Millan
authors: Mark E
authors: ME
authors: Bunnage
authors: Jane L
authors: JL
authors: Burrows
authors: Kenneth J
authors: KJ
authors: Butcher
authors: Peter G
authors: PG
authors: Dodd
authors: Timothy J
authors: TJ
authors: Evans
authors: David A
authors: DA
authors: Fairman
authors: Samantha J
authors: SJ
authors: Hughes
authors: Iain C
authors: IC
authors: Kilty
authors: Arnaud
authors: A
authors: Lemaitre
authors: Russell A
authors: RA
authors: Lewthwaite
authors: Axel
authors: A
authors: Mahnke
authors: John P
authors: JP
authors: Mathias
authors: James
authors: J
authors: Philip
authors: Robert T
authors: RT
authors: Smith
authors: Mark H
authors: MH
authors: Stefaniak
authors: Michael
authors: M
authors: Yeadon
authors: Christopher
authors: C
authors: Phillips
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D004285:Dogs; D004355:Drug Stability; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008782:Methylurea Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D020349:Surface Plasmon Resonance; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007191:Indazoles; D013440:Sulfides; D014230:Triazoles
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D053961:Azabicyclo Compounds; D008782:Methylurea Compounds; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C569762:N-(1-(3-chloro-4-hydroxyphenyl)-3-(1,1-dimethylethyl)-1H-pyrazol-5-yl)-N'-((2-((3-(2-((2-hydroxyethyl)thio)phenyl)-1,2,4-triazolo(4,3-a)pyridin-6-yl)thio)phenyl)methyl)-urea; D007191:Indazoles; D013440:Sulfides; D014230:Triazoles