IP Library › Granted Patent US 12,479,816
Granted Patent B2
US 12,479,816 · App. 17/429,289 · Granted Nov 25, 2025

20-HETE formation inhibitors

Inventors: Lee Apostle McDermott (Pittsburgh, PA); David Koes (Pittsburgh, PA); Samuel M. Poloyac (Pittsburgh, PA); Shabber Mohammed (Pittsburgh, PA)
Assignee: University of Pittsburgh—Of the Commonwealth System of Higher Education
C07D401/04C07D231/38C07D401/14C07D403/12C07D409/14C07D413/14
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Quick Facts
Patent No.
US 12,479,816
App. No.
17/429,289
Granted
Nov 25, 2025
Kind
B2
Abstract

This disclosure provides novel heterocyclic compounds and methods for inhibiting the enzyme CYP4. Further disclosed methods include: a method of inhibiting the biosynthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) in a subject in need thereof and a method of producing neuroprotection and decreased brain damage by preventing cerebral microvascular blood flow impairment and anti-oxidant mechanisms in a subject experiencing or having experienced an ischemic event.

Claims (121)

1 . A compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

X is

 wherein

each R 2 is independently selected from a group consisting of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocyclyl, C 1 -C 6 alkoxy, halo, —SR 3 , —S(O)R 3 , —CH 2 OR 3 , —(CH 2 )nS(O)R 3 , —(CH 2 ) n S(O) 2 R 3 , —SO 2 R 3 , —CO 2 R 3 , —SO 2 NHR 4 , —(CH 2 ) n —OR 4 , —OR 4 , —CO 2 R 4 , —NR 5 R 6 , —NR 5 C(O)R 6 , —(CH 2 ) n —NR 5 C(O)R 6 , —CH(CH 3 )—NR 5 C(O)R 6 , —CONR 5 R 6 , —N(R 5 )S(O) 2 R 6 , —N(R 5 )(CH 2 ) n S(O)R 6 , —N(R 5 )(CH 2 ) n S(O) 2 R 6 , —SO 2 NR 5 R 6 , and —NR 4 C(O)R 3 ,

R 3 is an optionally substituted C 1 -C 6 alkyl or an optionally substituted C 3 -C 6 cycloalkyl or an optionally substituted alkylene forming a 4, 5 or 6-member ring with the aromatic carbon atom adjacent to the location of the R 2 substituent,

R 4 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted tetrahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl,

R 5 and R 6 are each independently H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl; or R 5 and R 6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring, and

n and p are each independently 1, 2, or 3,

wherein when X is

 A, B and C are selected from —(C(R 2′ ) 2 ) 1-2 —, O, or SO 2 , wherein one of A, B and C is O or SO 2 , and wherein R 2′ is H or F, and

wherein when X is

 A, B and C are selected from —(C(R 2′ ) 2 ) 1-2 — or SO 2 , wherein one of A, B and C is SO 2 , and wherein R 2′ is H or F;

Y is a bond, O, S, S═O, SO 2 , or an optionally substituted methylene;

Z is CH; and

R 1 is

 wherein

Q is N or CH;

L is N, CH or CCH 3 , provided that L is not N when Q is N, and L is not CH or CCH 3 when Q is CH; and

M is H or CH 3 .

2 . The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein Y is a bond.

3 . The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein X is

and wherein:

each R 2 is independently selected from a group consisting of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocyclyl, C 1 -C 6 alkoxy, halo, —SR 3 , —S(O)R 3 , —CH 2 OR 3 , —(CH 2 ) n S(O)R 3 , —(CH 2 ) n S(O) 2 R 3 , —SO 2 R 3 , —CO 2 R 3 , —SO 2 NR 4 , —(CH 2 ) n —OR 4 , —OR 4 , —CO 2 R 4 , —NR 5 R 6 , —NR 5 C(O)R 6 , —(CH 2 ) n —NR 5 C(O)R 6 , —CH(CH 3 )—NR 5 C(O)R 6 , —CONR 5 R 6 , —N(R 5 )S(O) 2 R 6 , —N(R 5 )(CH 2 ) n S(O)R 6 , —N(R 5 )(CH 2 ) n S(O) 2 R 6 , —SO 2 NR 5 R 6 , and —NR 4 C(O)R 3 ,

R 3 is an optionally substituted C 1 -C 6 alkyl or an optionally substituted C 3 -C 6 cycloalkyl or an optionally substituted alkylene forming a 4, 5 or 6-member ring with the aromatic carbon atom adjacent to the location of the R 2 substituent,

R 4 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted tetrahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl,

R 5 and R 6 are each independently H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl; or R 5 and R 6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring, and

n and p are each independently 1, 2, or 3.

4 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein

X is

 and R 1 is

and wherein:

each R 2 is independently selected from a group consisting of H, F, Cl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocyclyl, —SR 3 , —S(O)R 3 , —SO 2 R 3 , —SO 2 NHR 4 , —OR 4 , —(CH 2 ) n —OR 4 , —CO 2 R 4 , —NR 5 R 6 , —NR 5 C(O)R 6 , —CONR 5 R 6 , —N(R 5 )SO 2 R 6 , and —SO 2 NR 5 R 6 ;

R 3 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 6 cycloalkyl;

R 4 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted tetrahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R 5 and R 6 are each independently H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl; or R 5 and R 6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

Y is O;

Z is CH;

Q is N or CH;

L is N, CH or CCH 3 , provided that L is not N when Q is N, and L is not CH or CCH 3 when Q is CH;

M is H or CH 3 ; and

n and p are each independently 1, 2, or 3.

5 . The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein:

X is

 and R 1 is

 and wherein:

each R 2 is independently selected from a group consisting of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocyclyl, C 1 -C 6 alkoxy, halo, —SR 3 , —S(O)R 3 , —CH 2 OR 3 , —(CH 2 ) n S(O)R 3 , —(CH 2 ) n S(O) 2 R 3 , —SO 2 R 3 , —CO 2 R 3 , —SO 2 NR 4 , —(CH 2 ) n —OR 4 , —OR 4 , —CO 2 R 4 , —NR 5 R 6 , —NR 5 C(O)R 6 , —(CH 2 ) n —NR 5 C(O)R 6 , —CH(CH 3 )—NR 5 C(O)R 6 , —CONR 5 R 6 , —N(R 5 )S(O) 2 R 6 , —N(R 5 )(CH 2 ) n S(O)R 6 , —N(R 5 )(CH 2 ) n S(O) 2 R 6 , —SO 2 NR 5 R 6 , and —NR 4 C(O)R 3 ;

R 3 is an optionally substituted C 1 -C 6 alkyl or an optionally substituted C 3 -C 6 cycloalkyl or an optionally substituted alkylene forming a 4, 5 or 6-member ring with the aromatic carbon atom adjacent to the location of the R 2 substituent;

R 4 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted tetrahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R 5 and R 6 are each independently H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl; or R 5 and R 6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

Y is S, S═O, or SO 2 ;

Z is CH;

Q is N or CH;

L is N, CH or CCH 3 , provided that L is not N when Q is N, and L is not CH or CCH 3 when Q is CH;

M is H or CH 3 ; and

n and p are each independently 1, 2, or 3.

6 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

X is

 and R 1 is

 and wherein:

each R 2 is independently selected from a group consisting of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocyclyl, C 1 -C 6 alkoxy, halo, —SR 3 , —S(O)R 3 , —CH 2 OR 3 , —(CH 2 ) n S(O)R 3 , —(CH 2 ) n S(O) 2 R 3 , —SO 2 R 3 , —CO 2 R 3 , —SO 2 NR 4 , —(CH 2 ) n —OR 4 , —OR 4 , —CO 2 R 4 , —NR 5 R 6 , —NR 5 C(O)R 6 , —(CH 2 ) n —NR 5 C(O)R 6 , —CH(CH 3 )—NR 5 C(O)R 6 , —CONR 5 R 6 , —N(R 5 )S(O) 2 R 6 , —N(R 5 )(CH 2 ) n S(O)R 6 , —N(R 5 )(CH 2 ) n S(O) 2 R 6 , —SO 2 NR 5 R 6 , and —NR 4 C(O)R 3 ;

R 3 is an optionally substituted C 1 -C 6 alkyl or an optionally substituted C 3 -C 6 cycloalkyl or an optionally substituted alkylene forming a 4, 5 or 6-member ring with the aromatic carbon atom adjacent to the location of the R 2 substituent;

R 4 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted tetrahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R 5 and R 6 are each independently H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl; or R 5 and R 6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

Y is CH 2 ;

Z is CH;

Q is N or CH;

L is N, CH or CCH 3 , provided that L is not N when Q is N, and L is not CH or CCH 3 when Q is CH;

M is H or CH 3 ; and

n and p are each independently 1, 2, or 3.

7 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

X is

 and R 1 is

 and wherein:

R 2 is selected from a group consisting of H, F, Cl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocyclyl, —OR 4 , —(CH 2 ) n —OR 4 , —CO 2 R 4 , —NR 5 R 6 , —NR 5 C(O)R 6 , —CONR 5 R 6 , and —N(R 5 )SO 2 R 6 ;

R 4 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted tetrahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R 5 and R 6 are each independently H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl; or R 5 and R 6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

Y is a bond or CH 2 ;

Z is CH;

Q is N or CH;

L is N, CH or CCH 3 , provided that L is not N when Q is N, and L is not CH or CCH 3 when Q is CH;

M is H or CH 3 ; and

n and p are each independently 1, 2, or 3.

8 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

X is

 and R 1 is

 and wherein:

R 2 is selected from a group consisting of H, F, Cl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocyclyl, —OR 4 , —(CH 2 ) n —OR 4 , —CO 2 R 4 , —NR 5 R 6 , —NR 5 C(O)R 6 , and —CONR 5 R 6 ;

R 4 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted tetrahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R 5 and R 6 are each independently H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl; or R 5 and R 6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

Y is a bond or CH 2 ;

Z is CH;

Q is N or CH;

L is N, CH or CCH 3 , provided that L is not N when Q is N, and L is not CH or CCH 3 when Q is CH;

M is H or CH 3 ; and

n and p are each independently is 1, 2, or 3.

9 . The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein:

X is

 and R 1 is

 and wherein:

each R 2 is independently selected from a group consisting of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocyclyl, C 1 -C 6 alkoxy, halo, —SR 3 , —S(O)R 3 , —CH 2 OR 3 , —(CH 2 ) n S(O)R 3 , —(CH 2 ) n S(O) 2 R 3 , —SO 2 R 3 , —CO 2 R 3 , —SO 2 NR 4 , —(CH 2 ) n —OR 4 , —OR 4 , —CO 2 R 4 , —NR 5 R 6 , —NR 5 C(O)R 6 , —(CH 2 ) n —NR 5 C(O)R 6 , —CH(CH 3 )—NR 5 C(O)R 6 , —CONR 5 R 6 , —N(R 5 )S(O) 2 R 6 , —N(R 5 )(CH 2 ) n S(O)R 6 , —N(R 5 )(CH 2 ) n S(O) 2 R 6 , —SO 2 NR 5 R 6 , and —NR 4 C(O)R 3 ;

R 3 is an optionally substituted C 1 -C 6 alkyl or an optionally substituted C 3 -C 6 cycloalkyl or an optionally substituted alkylene forming a 4, 5 or 6-member ring with the aromatic carbon atom adjacent to the location of the R 2 substituent;

R 4 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted tetrahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R 5 and R 6 are each independently H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl; or R 5 and R 6 and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

Y is S;

Z is CH;

Q is N or CH;

L is N, CH or CCH 3 , provided that L is not N when Q is N, and L is not CH or CCH 3 when Q is CH;

M is H or CH 3 ; and

n and p are each independently 1, 2, or 3.

10 . A compound selected from a group consisting of:

and a pharmaceutically acceptable salt or solvate thereof.

11 . A method of inhibiting the biosynthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof.

12 . A method of inhibiting CYP4, comprising contacting CYP4 with a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof.

13 . The method of claim 12 , wherein the contacting is in vitro.

14 . The method of claim 12 , wherein the contacting is in vivo in a subject in need.

15 . A method of producing neuroprotection and decreased brain damage by preventing cerebral microvascular blood flow impairment and anti-oxidant mechanisms in a subject experiencing or having experienced an ischemic event, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof.

16 . The method of claim 15 , wherein the ischemic event comprises trauma, focal ischemia (TFI), subarachnoid hemorrhage (SAH), vasoconstriction, thrombosis, embolism, cardiac arrest, stroke, aneurysm, hypertension, sickle cell disease, application of g-forces, arteriovenous malformation, peripheral artery occlusive disease, central nervous system (CNS) depressant overdose, or a combination thereof.

17 . A method of reducing the size or slowing the growth of kidney cysts by preventing 20-HETE formation and/or 20-HETE driven renal epithelial cell proliferation in a subject suffering from polycystic kidney disease, comprising administering a pharmacologically effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof.

18 . The method of claim 17 , wherein PKD is of the autosomal dominant or recessive type.

19 . The method of claim 11 , wherein the subject is a human.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 28, 2023
From: MCDERMOTT, LEE APOSTLE; KOES, DAVID; POLOYAC, SAMUEL M.; MOHAMMED, SHABBER
To: UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION
Reel/Frame 064415/0835 →
Continuity (2)
Provisional Application 62803398 · Feb 8, 2019
Related Publication 20220144797A1 · May 12, 2022
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