Sterol analogs in lipid nanoparticle formulations

A composition comprising a lipid nanoparticle (LNP), wherein the LNP comprises:

• (I) an ionizable lipid, wherein:
• (a) the ionizable lipid has a structure according to Formula CAT-I:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• p is an integer of between 1 and 9, inclusive;
• each instance of R2 is independently hydrogen or optionally substituted C1-6 alkyl;
• each instance of L is independently an optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene, or combination thereof,
• each instance of R6 and R7 is independently a group of formula (i), (ii), or (iii);
• Formulae (i), (ii), and (iii) are:
• wherein:
• each instance of R′ is independently hydrogen or optionally substituted alkyl;
• X is O, S, or NRX, wherein RX is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
• Y is O, S, or NRY, wherein RY is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
• RP is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom;
• and
• RL is optionally substituted C1-50 alkyl, optionally substituted C2-50 alkenyl, optionally substituted C2-50 alkynyl, optionally substituted heteroC1-50 alkyl, optionally substituted heteroC2-50 alkenyl, optionally substituted heteroC2-50 alkynyl, or a polymer;
• or
• (b) the ionizable lipid has a structure according to Formula CAT-II:
• or a pharmaceutically acceptable salt thereof,
• wherein:
• A1 is selected from
• wherein the left hand side of each depicted structure is bound to the —(CH2)a-;
• Z1 is selected from
• wherein the right hand side of each depicted structure is bound to the —(CH2)a-;
• R1A and R1B are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, and —W1—X1—Y1;
• each W1 is independently selected from optionally substituted alkyl and optionally substituted alkenyl;
• each X1 is independently selected from —*O—(C═O)-optionally substituted alkyl, —(*C═O)—O-optionally substituted alkyl, —*O—(C═O)-optionally substituted alkenyl, and —(*C═O)—O-optionally substituted alkenyl, wherein the atom marked with a * is connected to W1,
• each Y1 is independently selected from hydrogen, —*O—(C═O)-optionally substituted alkyl, —(*C═O)—O-optionally substituted alkyl, —*O—(C═O)-optionally substituted alkenyl, and —(*C═O)—O-optionally substituted alkenyl, wherein the atom marked with a * is connected to X;
• b is 1, 2, 3, 4, or 5;
• and
• each a is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• (II) a structural lipid, wherein said structural lipid is a sterol or sterol analog other than cholesterol;
• (III) optionally, cholesterol;
• (IV) a helper lipid;
• and
• (V) a stealth lipid.

A composition comprising a lipid nanoparticle (LNP), wherein the LNP comprises:

• (I) an ionizable lipid having a structure according to Formula CAT-V:
• or a pharmaceutically acceptable salt thereof,
• wherein L1 is a bond, (C1-C6) alkylene or (C2-C6) alkenylene;
• wherein X is O or S;
• wherein R1, R2, R3, R4 and R5 are each independently selected from H, OH, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted (C1-C6) alkoxy and —OC(O)R′;
• wherein at least one of R1, R2, R3, R4 or R5 is —OC(O)R′;
• wherein each R′ is independently selected from
• wherein R6 is
• wherein m and p are each independently 0, 1, 2, 3, 4 or 5;
• wherein each R7 is independently selected from H, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted (C1-C6) acyl, —(CH2)kRA or —(CH2)kCH(OR11)RA;
• wherein each R8 is independently selected from H, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted (C1-C6) acyl, —(CH2)nRB or —(CH2)nCH(OR12)RB;
• wherein R9 is selected from H, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted (C1-C6) acyl, —(CH2)qRC or —(CH2)qCH(OR13)RC;
• wherein R10 is selected from H, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, optionally substituted (C1-C6)acyl, —(CH2)rRD or —(CH2)rCH(OR14)RD;
• wherein k, n, q and r are each independently 1, 2, 3,4 or 5;
• or wherein (i) R7 and R8 or (ii) R9 and R10 together form an optionally substituted 5- or 6-membered heterocycloalkyl or heteroaryl wherein the heterocycloalkyl or heteroaryl comprises 1 to 3 heteroatoms selected from N, O and S;
• wherein R11, R12, R13 and R14 are each independently selected from H, methyl, ethyl or propyl;
• wherein RA, RB, RC and RD are each independently selected from optionally substituted (C6-C20) alkyl, optionally substituted (C6-C20) alkenyl, optionally substituted (C6-C20) alkynyl, optionally substituted (C6-C20) acyl, optionally substituted —OC(O) alkyl, optionally substituted —OC(O) alkenyl, optionally substituted (C1-C6) monoalkylamino, optionally substituted (C1-C6) dialkylamino, optionally substituted (C1-C6) alkoxy, —OH, —NH2;
• wherein at least one of R7, R8, R9, R10 comprises a RA, RB, RC or RD moiety respectively wherein that RA, RB, RC or RD is independently selected from optionally substituted (C6-C20) alkyl, optionally substituted (C6-C20) alkenyl, optionally substituted (C6-C20) alkynyl, optionally substituted (C6-C20) acyl, optionally substituted —OC(O)(C6-C20) alkyl or optionally substituted —OC(O)(C6-C20) alkenyl.
• (II) a structural lipid, wherein said structural lipid is a sterol or sterol analog other than cholesterol;
• (III) optionally, cholesterol;
• (IV) a helper lipid;
• and
• (V) a stealth lipid.