Modulators of G-protein coupled receptors

Inventors

ENQUIST, JOHAN • KRISHNAN, Shyam • ATWAL, SUMAN • Erlanson, Daniel • FUCINI, Raymond V. • Hansen, Stig • SAWAYAMA, ANDREW • Sethofer, Steven

Assignees

Cannot Therapeutics Inc

Abstract

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and/or hydrate and/or prodrug of the compound) that modulate (e.g., agonize or partially agonize or antagonize) glucagon?like peptide?1 receptor (“GLP?1R”) and/or the gastric inhibitory polypeptide receptor (“GIPR”). The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which modulation (e.g., agonism, partial agonism or antagonism) of GLP?1R and/or GIPR activities is beneficial for the treatment or prevention of the underlying pathology and/or symptoms and/or progression of the disease, disorder, or condition. In some embodiments, the modulation results in an enhancement of (e.g., an increase in) existing levels (e.g., normal or below normal levels) of GLP?1R and/or GIPR activity (e.g., signaling). In some embodiments, the chemical entities described herein further modulate (e.g., attenuate, uncouple)-arrestin signaling relative to what is observed with the native ligand. This disclosure also features compositions as well as other methods of using and making the said chemical entities.

Core Innovation

The invention relates to a compound having formula (IAA), or a pharmaceutically acceptable salt thereof, with a defined substituted ring system designated as ring A connected through a divalent group including G and N*. Ring A is constrained to a saturated or unsaturated monocyclic ring including from 3-8 ring atoms, or a saturated or unsaturated bicyclic or tricyclic ring including from 6-14 ring atoms, with G selected from C(O), S(O), or SO2 and the dotted, circular line connecting G and N* being a divalent group including from 1-6 ring atoms with defined heteroatom and carbon atom selections.

The compound further includes a linker group L defined by multiple structural alternatives, including forms corresponding to formula VIII and formula IX, as well as alternative (CH2)- and C(O)-containing variants. The linker includes specified linkage possibilities for X1, X2, and X3, selected from the listed groups such as carbonyl, oxygen, sulfur, sulfoxide, sulfone, arylene, heteroarylene, cycloalkylene, heterocycloalkylene, alkenylene, and alkynylene, together with defined parameter ranges for m, n, p, and related variables.

A peptide-conjugated portion is incorporated through the group −N(R4)W, where W is a peptide having formula (XIV) and SEQ ID NO: 2. The peptide sequence is represented as GTF(Xaa4)SD(Xaa7)S(Xaa9)(Xaa10)(Xaa11)(Xaa12)(Xaa13)QA(Xaa16)(Xaa17)(Xaa18)F-(Xaa20)(Xaa21)WL(Xaa24)(Xaa25)GGPSSGAPPPS-R5, with allowed residue options at each Xaa position, and R5 is a C-terminal amino acid, amino acid ester, or amino acid amide optionally substituted with from 1-2 modifying groups.

Claims Coverage

The consolidated claim coverage centers on one independent compound claim defining a highly specified chemical formula (IAA) with three main structural regions: ring A, the linker group L, and a peptide-conjugated portion defined by formula (XIV) (SEQ ID NO: 2). Dependent refinements further narrow ring-A form, linker parameters, and peptide variants, and the claim set also includes a method of modulating GLP-1R and/or GIPR activity by contacting the receptor with the claimed compound.

Overall, the claim coverage is directed to a tightly specified compound scaffold that combines a constrained ring A/divalent-group architecture, a defined linker group L, and a peptide-conjugated portion specified by SEQ ID NO: 2, with dependent narrowing and a receptor-modulation use claim.

Stated Advantages

Documented Applications