Neuroprotective chemicals and methods for identifying and using same

Patent metadata

Field	Value
Publication number	US-9645139-B2
Application number	US-201514945629-A
Country	US
Kind code	B2
Filing date	Nov 19, 2015
Priority date	Nov 11, 2013
Publication date	May 9, 2017
Grant date	May 9, 2017

Abstract

Provided herein are methods for identifying a compound having cell-protective (e.g., neuroprotective) activity. Compounds identified therefrom are also provided. These compounds can be used to treat various diseases, disorders, or conditions associated with, for example, unwanted cell death.

First claim

The invention claimed is:

1. A method for identifying a compound having cell-protective activity, comprising:
incubating a test compound with a nicotinamide phosphoribosyltransferase (NAMPT);
measuring an activity of the NAMPT; and
identifying the test compound as having cell-protective activity when there is an increase in the activity of the NAMPT compared to a control that is not incubated with the test compound, wherein the test compound is a compound having formula (I):

wherein:
each of R 1 , R 2 , R 3 , and R 4 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), nitro, —C(O)O(C 1 -C 6 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 alkyl), and —S(O) 2 N(C 1 -C 6 alkyl) 2 ;
R and R′ are defined according to (1), (2), (3) or (4) below:
(1) R and R′ together with C 2 and C 3 , respectively, form a fused phenyl ring having formula (II):

wherein each of R 5 , R 6 , R 7 , and R 8 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), nitro, —C(O)O(C 1 -C 6 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 alkyl), and —S(O) 2 N(C 1 -C 6 alkyl) 2 ; or
(2) R and R′ together with C2 and C3, respectively, form a fused heteroaryl ring containing 6 ring atoms, wherein from 1-2 independently selected ring atoms is N; and wherein said heteroaryl ring is optionally substituted with from 1-2 independently selected R b ; or
(3) R and R′ together with C 2 and C 3 , respectively, form a fused heterocyclic ring containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; and wherein said heterocyclic ring is optionally substituted with from 1-3 independently selected R a ; or
(4) each of R and R′ is, independently, hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each of L 1 and L 2 is, independently, C 1 -C 3 alkylene, which is optionally substituted with from 1-2 independently selected R c ;
A is:
(i) CR A1 R A2 , wherein each of R A1 and R A2 is independently selected from hydrogen, halo, C 1 -C 3 alkyl, OR 9 , wherein R 9 is hydrogen or C 1 -C 3 alkyl that is optionally substituted with hydroxyl or C 1 -C 3 alkoxy, or a double bond formed between A and one of L 1 and L 2 ; or
(ii) C⊚O; or
(iii) C 3 -C 5 cycloalkylene that is (a) substituted with 1 oxo; and (b) optionally further substituted with from 1-4 independently selected R a ; or
(iv) heterocycloalkylene containing from 3-5 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heterocycloalkylene is (a) substituted with 1 oxo; and (b) is optionally further substituted with from 1-4 independently selected R a ;

Z is:
(i) —NR 10 R 11 ; or
(ii) —C(O)NR 10 R 11 ; or
(iii) —OR 12 ; or
(iv) —S(O) n R 13 , wherein n is 0, 1, or 2; or
(v) heterocycloalkenyl containing from 5-6 ring atoms, wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; and wherein said heterocycloalkenyl is optionally substituted with from 1-4 independently selected R a ; or
(vi) C 6 -C 10 aryl that is optionally substituted with from 1-4 independently selected R b ; or
(vii) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 independently selected R b ; or
(viii) C 8 -C 14 arylcycloalkyl, wherein:
(1) the aryl portion is optionally substituted with from 1-4 independently selected R b , and
(2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ; or

(ix) arylheterocyclyl containing from 8-14 ring atoms, wherein:
(1) the aryl portion from is optionally substituted with from 1-4 independently selected R b , and
(2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ; or

(x) heteroarylheterocyclyl containing from 8-14 ring atoms, wherein:
(1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently selected R b ; and
(2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ; or

(xi) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein:
(1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently selected R b ; and
(2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;

each of R 10 and R 11 is independently selected from the substituents delineated collectively in (a) through (1) below:
(a) hydrogen;
(b) C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ;
(c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;
(d) C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, each of which is optionally substituted with from 1-3 R d ;
(e) —C(O) (C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), —C(O)O(C 1 -C 6 alkyl), —S(O) 2 (C 1 -C 6 alkyl), —S(O) 2 (C 6 -C 10 aryl), or —S(O) 2 (C 1 -C 13 heteroaryl), wherein the C 6 -C 10 aryl and C 1 -C 13 heteroaryl are each independently optionally substituted with 1-4 R b ;
(f) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
(g) C 8 -C 14 arylcycloalkyl, wherein:
(1) the aryl portion is optionally substituted with from 1-4 independently selected R b , and
(2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;

(h) arylheterocyclyl containing from 8-14 ring atoms, wherein:
(1) the aryl portion from is optionally substituted with from 1-4 independently selected R b , and
(2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ;

(i) heteroarylheterocyclyl containing from 8-14 ring atoms, wherein:
(1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently selected R b ; and
(2) from 1-2 of the ring atoms of the heteroc

Assignees

• Univ Texas

Inventors

• Mcknight Steven L
• Ready Joseph M
• Pieper Andrew A
• Wang Gelin
• Han Ting

Classifications

• G01N33/5014 Primary

  for testing toxicity · CPC title

• G01N2333/91142

  Pentosyltransferases (2.4.2) · CPC title

• G01N33/5058 Primary

  Neurological cells · CPC title

• G01N33/5038

  involving detection of metabolites per se · CPC title

• C12Q1/48

  involving transferase · CPC title