Synthesis and structure-activity relationships of beta- and alpha-piperidine sulfone hydroxamic acid matrix metalloproteinase inhibitors with oral antitumor efficacy.
alpha-Piperidine-beta-sulfone hydroxamate derivatives were explored that are potent for matrix metalloproteinases (MMP)-2, -9, and -13 and are sparing of MMP-1. The investigation of the beta-sulfones subsequently led to the discovery of hitherto unknown alpha-sulfone hydroxamates that are superior to the corresponding beta-sulfones in potency for target MMPs, selectivity vs MMP-1, and exposure when dosed orally. alpha-Piperidine-alpha-sulfone hydroxamate 35f (SC-276) was advanced through antitumor and antiangiogenesis assays and was selected for development. Compound 35f demonstrates excellent antitumor activity vs MX-1 breast tumor in mice when dosed orally as monotherapy or in combination with paclitaxel.
Becker
Daniel P
DP
Pfizer Research, 4901 Searle Parkway, Skokie, IL 60077, USA. dbecke3@luc.edu
Villamil
Clara I
CI
Barta
Thomas E
TE
Bedell
Louis J
LJ
Boehm
Terri L
TL
Decrescenzo
Gary A
GA
Freskos
John N
JN
Getman
Daniel P
DP
Hockerman
Susan
S
Heintz
Robert
R
Howard
Susan Carol
SC
Li
Madeleine H
MH
McDonald
Joseph J
JJ
Carron
Chris P
CP
Funckes-Shippy
Chris L
CL
Mehta
Pramod P
PP
Munie
Grace E
GE
Swearingen
Craig A
CA
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D005260:Female; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000401:mortality; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000627:therapeutic use; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C505981:N-hydroxy-4-((4-(phenylthio)phenyl)sulfonyl)-1-(2-propynyl)-4-piperidinecarboxamide; D010880:Piperidines; D013450:Sulfones; D017239:Paclitaxel